Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C.[C:53](Cl)(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:53]([N:40]1[CH2:41][CH2:42][N:37]([C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])[CH2:38][CH2:39]1)(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Reaction time: 16 h
Yield: 40.3 %

Procedure:
A solution of 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (30 mg, 47 μmol) and N,N-diisopropylethylamine (41 μL, 0.24 mmol) in dichloromethane was treated with benzoyl chloride (11 μL, 95 μmol) and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (14 mg, 40%) as a solid. LCMS for C29H27ClN6O (M+H)+: m/z=511.1. 1H NMR (400 MHz, DMSO-d6): δ 9.54 (br s, 1H), 9.38 (br s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.47-7.43 (m, 4H), 7.12-7.02 (m, 3H), 6.87-6.82 (m, 2H), 3.79 (br s, 2H), 3.49 (br s, 2H), 2.97 (s, 4H), 2.87-2.79 (m, 4H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][C:7]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:21]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]2[C:32]([CH2:33]Cl)=[CH:31][N:30]=[CH:29]2)=[CH:25][CH:24]=1)#[N:22].C(N(C(C)C)CC)(C)C>C(#N)C>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:28]2[C:32]([CH2:33][N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:17]=[CH:18][CH:19]=[C:3]([CH3:2])[CH:4]=4)([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]3)=[CH:31][N:30]=[CH:29]2)=[CH:35][CH:36]=1)#[N:22]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: COC(=O)C1(Cc2cccc(C)c2)CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
A solution of methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (142 mg, 0.5 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (135 mg, 0.5 mmol; Example 52, Step D), and diisopropylethylamine (0.26 mL, 1.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. After collection and concentration of appropriate fractions, the residue was recrystallized from a mixture of ethyl acetate and hexane to provide the title compound as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[F:19][C:20]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].C(N(CC)C(C)C)(C)C.C(Cl)CCl>CN(C=O)C>[F:19][C:20]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:21]=1[C:22]([NH:16][C:11]1[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:23]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C#N)cc2F)cc1
Reaction time: 48 h
Yield: 39.9 %

Procedure:
To a solution of N1-(4-methoxybenzoyl)-1,2-benzenediamine (0.5 g, 1.8 mmol), 2-fluoro-4-cyanobenzoic acid (0.3 g, 1.8 mmol) and N,N-diisopropylethylamine (0.23 g, 1.8 mmol) in DMF (5 mL) was added EDC (0.42 g, 2.2 mmol). After 48 h, 2-fluoro-4-cyanobenzoic acid (0.3 g, 1.8 mmol) and EDC (0.35 g, 1.8 mmol) were added. After an additional 24 h, the reaction was concentrated; and the residue was dissolved in ethyl acetate, washed with 1 N citric acid, brine, satd aq NaHCO3 and brine. The organic layer was MgSO4 dried, crystallized, filtered with ether wash, and dried under vacuum to give the title compound as a white solid 280 mg (40%); MS(FD): 389.1
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36](=[O:37])[CH2:35][N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CN1CCN(CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
The title compound, white solid (22.5 mg, 58.5%), MS (ISP) m/z=472.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2-(4-methylpiperazin-1-yl)acetic acid.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].C(=O)([O-])[O-:25].[Ca+2].[Br-].[Ca+2].[Br-]>O>[CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]([C@H:14]([OH:15])[C@@H:13]([OH:16])[C:12]([OH:17])=[O:11])[C@H:10]([OH:25])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C([O-])[O-]
Agent: [Br-]
Agent: [Ca+2]
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 8 °C
Reaction time: 8 h

Procedure:
Maltose (1 kg, 2.92 moles) is dissolved into 3.8 l, deionized water with heating, in the range of about 40° C. to 60° C., or sufficient to dissolve the maltose. Calcium carbonate (381 g, 3.81 moles) and calcium bromide (51 g, 0.26 mole) are added with mixing. The solution is poured into an electrolysis chamber equipped with a cooling loop and cooled. Six volts DC are applied to opposite graphite electrodes. At 8 hour intervals, the potential is reversed. After 24 h, maltose (1 kg, 2.92 moles) is added and electrolysis is continued until essentially all of the maltose is converted to its acid form (as measured by HPLC), about 104 h total time. The solution is filtered to remove excess calcium carbonate and the pH of the filtrate is adjusted to 2.0 with sulfuric acid. The solution is cooled about 12 to 16 h to 8° C., and filtered to remove calcium sulfate. Calcium ions are removed by batch adsorption to Amberlite IRA 120 resin in the hydrogen form. The sulfate and bromide ions are removed by batch adsorption to Amberlite IRA 68 resin in the hydroxide form. The solution is spray dried with a Bowen 3 ft (1 m) flat bottom laboratory spray drier with a 2 fluid nozzle atomizer. The inlet temperature is kept at about 280° F. to 300° F. (138° C. to 149° C.) with all ports closed. The cellobionic acid is produced in the same manner from cellobiose.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]=O)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].N1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.[CH3:54][O:55][NH2:56]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH:35]=[N:56][O:55][CH3:54])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 64.5 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-oxoethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (145 mg, 0.25 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.099 mL, 1.28 mmol), sodium acetate (201.3 mg, 2.45 mmol) and O-methylhydroxylamine hydrochloride (102 mg, 1.22 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (50 mL). The organic layer was separated, washed with water (2×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.8:8.2 Acetone:Pet. Ether) to afford title compound (100 mg, 64.4%).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].S(=O)(=O)(O)O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([F:27])[C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20].BrCC#N>C1COCC1>[C:1]([CH2:2][NH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([F:27])[C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20])#[N:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc(N)c(C)c(F)c1
Agent: N#CCBr
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(C)c(NCC#N)c1
Temperature: 55 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of N,N-diisopropylethylamine (187 mL, 1073.6 mmol) in THF (240 mL) at 60-65° C. was added a solution of methyl 3-amino-5-fluoro-4-methylbenzoate sulfuric acid salt (80.0 g, 268.8 mmol) in THF (720 mL), maintaining the temperature in the range 45-65° C. Bromoacetonitrile (56.2 mL, 806.8 mmol) was charged and the solution heated to reflux for 3 d before concentration to 8 rel. vols. by distillation at atmospheric pressure. The solution was cooled to ambient temperature and water (1000 mL) added, maintaining the temperature in the range 18-23° C. The pH was adjusted to 1.2-1.5 with aq. hydrochloric acid (4 M, ˜80 mL) and the resulting slurry stirred at ambient temperature for 2 h before being filtered through 100 μm filter cloth under nitrogen. The filter cake was washed with mixed heptanes (2×320 mL) and dried under nitrogen at up to 45° C. to afford methyl 3-(cyanomethylamino)-5-fluoro-4-methylbenzoate (54.9 g, 99.1% w/w).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[CH3:16]O>>[CH3:16][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([NH2:6])=[CH:8][CH:9]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
Concentrated sulfuric acid was slowly added to a mixture of 4-aminobenzoic acid (4 g, 29.2 mmol) in methanol cooled to 0° C. After the addition, the mixture was stirred at room temperature for 5 hours. The mixture was washed with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under vacuum to obtain 4-aminobenzoic acid methyl ester (49a) (4.22 g, 27.9 mmol, 96%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([O:10][CH3:11])[CH:3]=1.C([N:14](CC)CC)C.[C:19]([CH2:23][C:24](Cl)=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([CH:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:24]([NH2:14])=[O:25])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1N
Reactant: CCN(CC)CC
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Product: COc1cc(Br)cc(C)c1C(C(N)=O)C(C)(C)C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of 4-bromo-2-methoxy-6-methyl-aniline (2.2 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butylacetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature, than the reaction mixture was diluted with dichloromethane and washed with water and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (2.8 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:27])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](=[O:18])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:41])([F:40])[F:28])=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cc2)cs1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 80.5 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(4-bromophenyl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 458-1 and 4-trifluoromethylphenylboric acid (363 mg) were dissolved in dioxane (8 mL) and 2M aqueous sodium carbonate solution (4 mL), tetrakis(triphenylphosphine)palladium (73 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (550 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:27]([CH2:29][CH3:30])[CH3:28]>>[CH:27]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])([CH2:29][CH3:30])[CH3:28]
Reactant: CCC(C)Br
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Product: CCC(C)Oc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC

Procedure:
Using the compound obtained in Example 136 and 2-bromobutane, yellow oily 3-[2-(3-sec-butoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[OH:8][C:7]1[C:4]([O:5][CH3:6])=[CH:3][C:2]([C:1]([OH:12])=[O:11])=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reaction time: 1 h
Yield: 40 %

Procedure:
The process of Example 1a was scaled up to employ vanillic acid (375 g) in acetic acid (3940 g) to which was added nitric acid (65%, 245 g) at 12° C. over 3 hours followed by stirring for one hour. The overall yield was 40% of a 99.9% pure product.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]2[C:10]=1[C@@H:9](O)CC2.O[C:19]1C=CC2[C@H](CC(OC)=O)COC=2C=1.Br[C:34]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]2[C:35]=1[CH2:36][CH2:37][C@H:38]2[O:44][C:45]1[CH:58]=[CH:57][C:48]2[C@H:49]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH2:50][O:51][C:47]=2[CH:46]=1>>[CH3:19][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:6]=[C:10]([CH3:9])[C:2]=1[C:34]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]2[C:35]=1[CH2:36][CH2:37][C@H:38]2[O:44][C:45]1[CH:58]=[CH:57][C:48]2[C@H:49]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH2:50][O:51][C:47]=2[CH:46]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: O[C@H]1CCc2c(C3CCOCC3)ccc(F)c21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C6CCOCC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (S)-7-fluoro-4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-inden-1-ol and (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 3 of Intermediate 1. LC (method 26): tR=0.95 min; Mass spectrum (ESI+): m/z=531 [M+H]+.
Reaction SMILES: [Cl-:1].[NH4+:2].C[Al](C)C.[C:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)#[N:8]>C1(C)C=CC=CC=1.CCCCCC.C(Cl)Cl>[ClH:1].[C:9]1([C:7](=[NH:2])[NH2:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: N#Cc1cccc2ccccc12
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cl
Product: N=C(N)c1cccc2ccccc12
Temperature: 0 °C

Procedure:
14 g (261 mmol, 2 equiv.) ammonium chloride are suspended in 150 ml of dry toluene under an argon atmosphere, and the mixture is cooled to 0° C. 130 ml (260 mmol, 2 equiv.) of a 2M solution of trimethylaluminium in hexane are added dropwise, and the reaction mixture is stirred at room temperature until no more evolution of gas is observed. After addition of 20 g (130 mmol, 1 equiv.) 1-cyano-naphthalene, the mixture is stirred at 80° C. bath temperature over night. The mixture is cooled and poured into a slurry of silica in methylene chloride. After filtration, the solid is washed with methanol for several times, the solution is evaporated to dryness in vacuo and the residue washed with methanol. The combined filtrates are pooled and stirred in a mixture of methylene chloride containing 10% methanol.
Reaction SMILES: Br[CH:2]([C:6]1[S:7][C:8]([C:17]2[N:21]=[CH:20][N:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:3]([CH3:5])=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1.C(=O)(O)[O-].[Na+].CCOC(C)=O>C1COCC1.CC(O)C>[Br:35][C:32]1[CH:33]=[CH:34][C:29]2[N:30]([C:2]([C:6]3[S:7][C:8]([C:17]4[N:21]=[CH:20][N:19]([CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)[N:18]=4)=[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:10]=3)=[C:3]([CH3:5])[N:28]=2)[CH:31]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)C(Br)c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
To a solution of 1-bromo-1-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}acetone (2.96 g, 6.6 mmol) obtained in Example 116-B(vi) in THF (33 mL) and 2-propanol (33 mL), was added 2-amino-5-bromopyridine (5.71 g, 33.0 mmol), and the mixture was stirred at 80° C. for 3 h. The reaction mixture was allowed to cool to rt, and then were added saturated aqueous solution of sodium bicarbonate (60 mL) and EtOAc (150 mL). The aqueous layer was extracted with EtOAc (80 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=20/80→100/0; then MeOH/EtOAc=20/80), and then basic silica gel column chromatography (EtOAc/hexane=10/90→80/20) to give the title compound (520 mg, 15%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[F:9][C:10]([F:27])([F:26])[CH2:11][N:12]=[C:13]([NH2:25])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:19]=1.C(Cl)(Cl)Cl.CO.N>C(#N)C>[F:27][C:10]([F:9])([F:26])[CH2:11][N:12]=[C:13]([NH2:25])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])[N:19]=1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: FC(F)(F)CN=C=S
Agent: N
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNC(=S)NCC(F)(F)F)cs1
Reaction time: 2 h

Procedure:
Trifluoroethylisothiocyanate (0.2 g.) in acetonitrile (6 ml.) was added to a solution of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.5 g.) in acetonitrile (10 ml.), and the mixture was allowed to stand at room temperature for 2 hours. The residue obtained on evaporation of the solvent was subjected to preparative thin layer chromatography using chloroform/methanol/ammonia 85:15:0.5 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (200 ml.). The residue was crystallised from ethyl acetate/light petroleum ether (b.p. 60°-80°) to give 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-(4-[3-(2,2,2-trifluoroethyl)thioureido]butyl)-thiazole. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (δ):4.05 (2H, multiplet); 4.35 (2H, multiplet); 6.36 (1H, singlet).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH2:9]([NH:12][CH3:13])[CH:10]=[CH2:11]>CC(N(C)C)=O>[CH2:9]([N:12]([CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH:10]=[CH2:11].[BrH:1]
Reactant: OCCCCCCBr
Reactant: C=CCNC
Solvent: CC(=O)N(C)C
Product: Br
Product: C=CCN(C)CCCCCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 ml of 1-bromo-6-hexanol are taken up in DMA, treated with 1.47 ml of N-allyl-methyl-amine and stirred at RT for 16 h. The reaction mixture is concentrated and the residue is lyophilized overnight. There are obtained 1.9 g of 6-(allyl-methyl-amino)-hexan-1-ol•hydrobromide as the crude product, MS: m/e 171 (M).