Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:20])=[C:9]([NH2:19])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](O)(=O)[CH:22]([CH3:24])[OH:23].Cl>>[C:13]1([C:10]2[C:9]3[N:19]=[C:21]([CH:22]([OH:23])[CH3:24])[NH:20][C:8]=3[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(O)C(=O)O
Reactant: Nc1c(-c2ccccc2)ccc(-c2ccccc2)c1N
Agent: Cl
Product: CC(O)c1nc2c(-c3ccccc3)ccc(-c3ccccc3)c2[nH]1
Temperature: 140 °C
Yield: 82.8 %

Procedure:
A mixture of 1.25 g (4.8 mmol) 1,1′:4′,1″-terphenyl-2′,3′-diamine, 0.75 ml (8.6 mmol) 85% aq. lactic acid and 4.8 ml 4N HCl were stirred at reflux for 6 hours and then the volatile materials evaporated over 1 hour. The oily residue was heated to 140° C. and stirred for 15 min. After cooling to room temperature 10 ml water were added and the mixture triturated for 30 min. Addition of conc. NH4OH to pH˜7.5–8 followed by filtration, washing with water (4×10 ml) and drying under vacuum at 60° C. gave 1.25 g (82.8%) of the desired product. 1H NMR (250 MHz, CDCl3), δ, ppm: 1.58 (d, JHH=6.7 Hz, 3H), 3.64 (br.s, 1H), 5.07 (q, 1H), 7.37–7.76 (m, 12 H), 9.53 (br. s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1.[C:14](=[O:21])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:15].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:17]([O:16][C:14]([NH:15][C:2]1[CH:11]=[C:10]([F:12])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(N)=O
Reactant: COC(=O)c1c(F)cc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1c(F)cc(NC(=O)OC(C)(C)C)cc1F
Temperature: 140 °C
Reaction time: 0.03 h

Procedure:
Under argon, a microwave vessel was charged with 54 mg (0.22 mmol) of methyl 4-bromo-2,6-difluorobenzoate, 118 mg (1.01 mmol, 4.7 eq.) of tert-butyl carbamate, 4.6 mg (0.02 mmol, 0.1 eq.) of palladium(II) acetate, 15 mg (0.026 mmol, 0.13 eq.) of Xantphos, 137 mg (0.42 mmol, 2 eq.) of caesium carbonate and 2 ml of 1,4-dioxane. A stream of argon was passed through the suspension for 2 min. The reaction mixture was heated in the microwave at 140° C. for 20 min. After filtration through kieselguhr, the filtrate was concentrated under reduced pressure. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 10-50% mixtures). Yield: 37 mg (60% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13]>C(O)CCCC.CCOCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[N:3]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Solvent: CCCCCO
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Yield: 101 %

Procedure:
2,6-Dichloro-9H-purine (650 mg, 3.44 mmol) and 3-nitroaniline (1.9 g, 13.76 mmol) were stirred in 1-pentanol (5 mL) at 100° C. for 2 h under N2. The mixture was cooled and diluted with Et2O (40 mL). The precipitate was filtered and washed successively on a sinter with Et2O, PriOH, H2O, 10% aq Na2CO3, H2O, PriOH, and Et2O (2×20 mL each). It was then dried in vacuo to afford the title compound as a lemon-yellow powder (1.01 g, quant.). TLC (9:1 CH2Cl2/MeOH): RF=0.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]1[O:13][CH:11]1[CH3:12]>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC1CO1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
General Procedure FF: To a THF (5 mL) solution of 1.0 M of 4-chlorophenylmagnesium bromide in Et2O (10.0 mL) was added a solution of propylene oxide (0.87 g, 15 mmol) in THF (5 mL) at −78° C. under nitrogen and stirred. The mixture was slowly warmed to rt. The mixture was quenched with sat. aq NH4Cl (10 mL) and then extracted with EtOAc (50 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.23-1.26 (m, 3H), 1.44 (d, J=3.8 Hz, 1H), 2.65-2.80 (m, 2H), 3.97-4.07 (m, 1H), 7.14-7.18 (m, 2H), 7.28-7.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[Cl:1][C:2]1[S:3][C:4]([C:11]([O:17][CH:14]([CH3:16])[CH3:15])=[O:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: CC(C)O
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Product: CC(C)OC(=O)c1sc(Cl)nc1C(F)(F)F
Yield: 86.1 %

Procedure:
The acid chloride of Example 16 (5.2 g), and 10 g of isopropanol were held at reflux for 16 hours. Excess alcohol was removed under reduced pressure. The residue was dissolved in 50 ml. of ether. The ether solution was washed with sodium bicarbonate, dried (MgSO4) and concentrated under reduced pressure. The crude product was distilled at 1 mm. on a Kugelrohr to give 4.9 g (86%) of the desired product as colorless liquid, nD25 =1.4655.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=[O:11])[CH2:3][CH2:2]1.[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([N:1]4[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10](=[O:11])[NH2:12])[CH2:3][CH2:2]4)=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: NC(=O)CCCC1CCNCC1
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(CCCC(N)=O)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(Piperidin-4-yl)butanamide (547 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (3 ml); phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (210 mg, 0.402 mmol, the product of Production example 5-2) was added thereto; and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The obtained amorphous solid was crystallized by adding diethyl ether. After addition of a small amount of ethanol to make a suspension, this was diluted with hexane. After separation by filtration to obtain crystals, these were rinsed with diethyl ether and dried under aeration. Thus, the title compound was obtained as colorless crystals (157 mg, 0.328 mmol, 81.7%).
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[N:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=[C:35]=[O:36])(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:37][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35](=[O:36])[O:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([N:11]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]([C:21]([F:23])([F:24])[F:22])=[N:10]3)=[CH:13][CH:14]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: OCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3nc(C(F)(F)F)cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 2-{4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethanol (step 1, 158 mg, 0.48 mmol) in dichloromethane (10 ml) was added p-toluenesulfonyl isocyanate (114 mg, 0.58 mmol). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture washed with water and the organic phase was dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with toluene/ethanol (10:1) to afford 184 mg (73%) of the title compound as yellow solids: MS (ESI) m/z 530 [M+H]+, 528 [M−H]−, 1H-NMR (CDCl3) δ 7.87-7.80 (3H, m), 7.36-7.09 (10H, m), 6.75 (1H, s), 4.28 (2H, t, J=6.1 Hz), 2.91 (2H, t, J=6.9 Hz), 2.42 (3H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[OH-].[Na+]>C1COCC1>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC2(CC1)OCCO2
Reaction time: 0.83 h
Yield: 103.4 %

Procedure:
The procedure of Pearson at al., J. Org. Chem., 1997, 62, 5284 was followed. To a stirred 1M solution of lithium aluminum hydride (148 mL, 148 mmol) cooled to 0° C., in an ice-bath, was added a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (31.8 g, 148 mmol) in THF (30 mL), dropwise, over a period of 50 min. The ice-bath was removed and the mixture stirred under N2 overnight. It was then cooled and water (20 mL) slowly added under vigorous stirring [note: very vigorous reaction with heat and foam generation] followed by the addition of 15% NaOH (20 mL). The insoluble material was removed by filtration through CELITE®, washing with THF. The combined filtrate and washings were dried (Na2SO4), filtered and concentrated to provide the title compound, 1,4-dioxaspiro[4.5]decan-8-ylmethanol (26.3 g, 153 mmol, 103% yield) as a clear oil: LCMS: m/z 173 (M+H) at 0.67 min; 1H NMR (500 MHz, CDCl3) δ ppm 1.11-1.25 (2H, m), 1.39-1.52 (3H, m), 1.70 (4H, d, J=9.5 Hz), 2.75 (1H, s), 3.39 (2H, d, J=6.4 Hz), 3.86-3.89 (4H, m); 13C NMR (126 MHz, CDCl3) δ ppm 26.7, 34.2, 39.1, 64.3, 67.5, 109.2.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[N:27]2[C:22]([CH2:23][O:24][CH2:25][CH2:26]2)=[CH:21][C:20]=1[C:28](O)=[O:29]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:20]3[CH:21]=[C:22]4[CH2:23][O:24][CH2:25][CH2:26][N:27]4[N:19]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc2n(n1)CCOC2
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc2n(n1)CCOC2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid (166 mg, 0.997 mmol). The product was triturated with acetonitrile. Yield 95 mg (46%). 1H-NMR (400 MHz; d6-DMSO): δ 1.09 (d, 3H), 4.09 (t, 2H), 4.18 (t, 2H), 4.26-4.39 (m, 2H), 4.42-4.49 (m, 1H), 4.79 (s, 2H), 6.38 (s, 1H), 6.95 (d, 1H), 7.82 (d, 1H), 7.97-7.99 (m, 2H), 8.09 (s, 1H), 8.26 (d, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=O.[CH2:12]([O:14][C:15]([C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)=[O:16])[CH3:13]>CC(CC)=O>[Cl:11][C:8]1[N:7]=[N:6][C:5]([C:3]2[N:22]=[C:19]3[N:18]([CH:2]=2)[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:21][S:20]3)=[CH:10][CH:9]=1
Reactant: O=C(CBr)c1ccc(Cl)nn1
Reactant: CCOC(=O)c1csc(N)n1
Solvent: CCC(C)=O
Product: CCOC(=O)c1csc2nc(-c3ccc(Cl)nn3)cn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a 20 dram vial was added 2-bromo-1-(6-chloropyridazin-3-yl)ethanone (4.2 g, 18 mmol), ethyl-2-aminothiazole-4-carboxylate (3.1 g, 18 mmol), and methylethylketone (40 mL). The mixture was heated to 90° C. and stirred overnight. The reaction was then concentrated and purified by silica gel chromatography (EtOAc/hex) to afford 1.0 g of ethyl 6-(6-chloropyridazin-3-yl)imidazo[2,1-b]thiazole-3-carboxylate as a yellow solid.
Reaction SMILES: [OH-].[K+].[OH:3][NH:4]C(=O)OC(C)(C)C.[N+]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:16]=1[C:17]#[N:18])([O-])=O.O>CN(C=O)C>[NH2:18][C:17]1[C:16]2[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=[CH:22][C:15]=2[O:3][N:4]=1
Reactant: CC(C)(C)OC(=O)NO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1noc2cccc([N+](=O)[O-])c12
Reaction time: 20 h
Yield: 21.7 %

Procedure:
To potassium hydroxide (0.58 g, 10.3 mmol) and tert-butyl N-hydroxycarbamate (1.38 g, 10.3 mmol) in DMF (30 iml) was added 2,6-dinitrobenzonitrile (2.0 g, 10.3 nmmol) and the mixture was stirred for 20 h. Water was added. The whole was extracted with ether, the ether was dried (sodium sulphate) and evaporated. Flash column chromatography on silica gel, eluting with ethyl acetate/dichloromethane, gave the product (0.4 g), MS (+CI) 180 ([M+H]+), 1H NMR (CDCl3) 8.13 (1H, d), 7.78 (1H, d), 7.68 (1H, dd), 5.43 (2H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][C:15]([NH2:24])([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:16]>ClCCl.C(OCC)(=O)C>[CH3:16][C:15]([NH:24][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])([CH3:14])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CC(C)(N)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Quinoxaloyl chloride (207 mg, 1.07 mmol) in dichloromethane (1 mL) was added to a solution of phentermine (160 mg, 1.07 mmol) in dichloromethane (3 mL) cooled to 0° C.The reaction was allowed to warm to 25° C.After 5 min, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with 1 M sodium hydroxide (2×40 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through silica gel, and rotary evaporated. This provided 51 mg (16%) of (108):
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH2:9][OH:10])=[CH:5][CH:6]=1.[OH-:11].[K+:12]>C1(C)C=CC=CC=1>[C:9]([O-:11])(=[O:10])[CH:8]=[CH:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1.[K+:12]
Reactant: OC/C=C/c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C([O-])C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g (0,36 mol) of cinnamic alcohol are dissolved in 180 ml of dry toluene. 20 g (0,36 mol) of KOH are added to the solution, and the resulting mixture is kept under stirring for one hour at room temperature. During this phase, potassium cinnamate is obtained. Then, a solution prepared starting from 18 g (0,10 mol) of 2,4,6-trichloro-s-triazine in 150 ml of toluene is added, allowing to react at room temperature for further 90 hours under stirring.
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:9][CH:8]([CH3:10])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:33]=4[N:34]=3)=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:40])=[O:5]
Reactant: Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.2 %

Procedure:
To (S)-3-methyl-2-{4′-[(4-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester (135 mg) was added 4 mL of TFA/CH2Cl2 (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 140 mg of (S)-3-methyl-2-{4′-[(4-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 7.4 (d, J=8.3 Hz, 1 H) 7.5 (m, 1 H) 7.7 (d, J=8.3 Hz, 1 H) 7.8 (m, 6 H) 8.1 (t, J=8.8 Hz, 3 H) 11.3 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][F:29].O>C(Cl)(Cl)Cl>[F:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2nc(-c3ccc(OCCCF)cc3)cn2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
242 mg (corresponding to 1.0 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 10 L of N,N-dimethylformamide, and 418 mg (corresponding to 3.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 140 μL (corresponding to 1.5 mmol) of 1-bromo-3-fluoropropane, and then was stirred at room temperature for 18 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed once with water and once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name: manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 189 mg (corresponding to 0.63 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-methoxyimidazo[1,2-a]pyridine (hereinafter referred to as Compound 1) (FIG. 2, Step 6).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:65]2[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[C:67]([C:73]([F:76])([F:75])[F:74])[CH:66]=2)[CH2:60][CH2:59]1>CN(C)C=O.ClCCl.O1CCCC1>[F:76][C:73]([F:74])([F:75])[C:67]1[CH:66]=[C:65]([NH:64][CH:61]2[CH2:62][CH2:63][N:58]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:22])([F:23])[F:2])=[CH:9][CH:8]=4)[CH2:11][CH2:12]3)[CH2:59][CH2:60]2)[CH:72]=[CH:71][C:68]=1[C:69]#[N:70]
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: N#Cc1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in, prepared in accordance with Example 3), diisopropylethyl amine (25 μL; 0.15 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of 4-(piperidin-4-ylamino)-2-trifluoromethyl-benzonitrile hydrochloride (15 mg; 0.05 mmol) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 2 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (23 mg; 0.04 mmol). The structure was confirmed using Protocol I-B. Calculated mass=568; observed mass=568; HPLC retention time=5.10 min.
Reaction SMILES: [C:1]([O:14][CH2:15][CH:16]([CH2:18]O)O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)CC[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[C:1]([O:14][CH2:15][CH2:16][CH2:18][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC(=O)OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC

Procedure:
Example 2 was repeated but for the sequence of addition of glycerol monolaurate. Instead of being added with cetyl alcohol, an equal amount of glycerol monolaurate utilized in Example 2 was added after the addition of the TEA.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[C:18]([F:20])[C:14]([C:15]([NH2:17])=O)=[C:13]([F:21])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C=O)C>[C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([F:21])[C:14]([C:15]#[N:17])=[C:18]([F:20])[CH:19]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCc1cc(F)c(C(N)=O)c(F)c1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1cc(F)c(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
To a stirred solution of the above benzamide intermediate (1.5 g, 5.0 mmol) in DMF (15 mL) at 0° C. was added cyanuric chloride (0.461 g, 2.5 mmol). The reaction was stirred at 0° C. for 40 min. Water (50 mL) was added and the mixture was extracted with dichloromethane, dried with sodium sulfate and concentrated. Chromatography on silica gel (ether/hexane, 1:1) afforded 4-(N-boc-2-aminoethyl)-2,6-difluorobenzonitrile (1.1 g, 3.9 mmol, 78%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(N=C=S)=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]([NH:33][NH2:34])=[O:32])=[CH:22]1>>[C:1]1([NH:7][C:8]([NH:34][NH:33][C:31](=[O:32])[CH2:30][C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][CH:22]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)Cc1c[nH]c2ccccc12
Reactant: S=C=Nc1ccccc1
Agent: COc1ccc(N=C=S)cc1
Product: O=C(Cc1c[nH]c2ccccc12)NNC(=S)Nc1ccccc1
Yield: 72.9 %

Procedure:
By substituting 1.5 g of phenylisothiocyanate for the 4-methoxyphenylisothiocyanate and 2 g of 2-(indol-3-yl)acetic acid hydrazide for the thien-2-carboxyhydrazide in the method of Example 97, 2.5 g of the title compound is obtained as an off-white solid.
Reaction SMILES: C1(CN2CCC(C[CH2:15][C:16]3[C:20]4[CH:21]=[C:22]5[NH:27][C:26](=[O:28])[CH2:25][C:23]5=[CH:24][C:19]=4[O:18][N:17]=3)CC2)C=CC=CC=1.N1C=CC=CC=1>CN(C=O)C>[CH3:15][C:16]1[C:20]2[CH:21]=[C:22]3[NH:27][C:26](=[O:28])[CH2:25][C:23]3=[CH:24][C:19]=2[O:18][N:17]=1
Reactant: O=C1Cc2cc3onc(CCC4CCN(Cc5ccccc5)CC4)c3cc2N1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1noc2cc3c(cc12)NC(=O)C3
Yield: 11.9 %

Procedure:
The procedure described in Example 33d was followed with the oxime acetate obtained in step c (2.75 g, 10.97 mmol) and pyridine (8.9 mL, 109.7 mmol) in DMF (110 m). After concentration in vacuo, the residue was purified by silica gel flash chromatography (2% MeOH—CH2Cl2) to give the title compound (0.245 g, 12%) as a pastel yellow solid.