Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccco1
Reactant: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 48 (363 mg, 1 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 332 mg (73%) of white solids. M.P. 209° C. 1H NMR (DMSO-d6): δ 3.69 (m, 4H), 3.97 (m, 4H), 5.49 (s, 2H), 6.66 (m, 1H), 7.09 (d, J=3.3 Hz, 1H), 7.22 (m, 3H), 7.32 (m, 2H), 7.45 (dd, J=4.7, 9.5 Hz, 1H), 7.55 (m, 1H), 7.69 (dd, J=2.8, 9.7 Hz, 1H), 7.88 (s, 1H). EIMS m/z 479 (M+23). Anal. (C26H21FN4O3) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[C:10]1[CH:34]=[CH:33][C:13]([CH2:14][C:15]([C:17]2[N:18]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:19]=[C:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:21]=2)=[CH2:16])=[CH:12][CH:11]=1.[SnH4]>COCCOC.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>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:20]1[N:21]=[C:17]([C:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=3)=[CH:34][CH:33]=2)=[CH2:16])[N:18]([S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:19]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C=C(Cc1ccc(Br)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SnH4]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C=C(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Pd(PPh3)4 (196 mg) was added to a solution of 2-bromo-5-fluoropyridine in DME (10 mL) at ambient temperature. After heating at 90° C. overnight the reaction mixture was cooled. 2-[1-(4-bromobenzyl)vinyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (110 mg) was added to the stannane solution followed by Pd(PPh3)4 (100 mg). After stirring at 95° C. overnight, the reaction mixture was cooled, diluted with ethyl acetate and washed with water. The organic phase was dried (sodium sulfate) and concentrated. Chromatography of the resulting crude product over silica eluting with 0-50% ethyl acetate/hexanes afforded 4-(2,2-dimethylpropyl)-2-{1-[4-(5-fluoropyridin-2-yl)benzyl]vinyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [O:1]1[CH2:5][C:2]1([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]#[CH:4].O>OS(O)(=O)=O.C(O)C>[F:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: C#CC1(c2ccc(F)cc2)CO1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2ccco2)cc1
Temperature: 23 °C
Yield: 57.7 %

Procedure:
To a solution of 0.7 g HgSO4 in 40 mL of 2N H2SO4 was added 5.0 g (31 mmol) of the 3,4-epoxy-3-(4'-fluorophenyl)-1-butyne in 40 mL of absolute ethanol, dropwise. The reaction mixture was refluxed for 0.25 hour and cooled to 23° C. After addition to 50 mL of H2O, the aqueous phase was extracted twice with hexanes. The hexane layers were combined, dried (MgSO4) and concentrated under reduced pressure. Sublimation (90° C. at 0.2 mmHg) of the residue yielded 2.9 g (58%) of the 2-(4'-fluorophenyl)furan as a solid (m.p. 84°-86° C.) homogeneous by spectroscopic criteria; IR (film) 1571, 1505, 1223, 1152, 785 cm-1 ; 1HNMR (80 MHz, CDCl3) 7.5-7.0 (m, 6H), 6.65 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]=[N+]=[N-])[CH:13]([OH:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(S)CCS>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[CH:13]([OH:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC1CCCN(C(=O)OCc2ccccc2)CC1O
Agent: SCCCS
Solvent: CO
Solvent: CCN(CC)CC
Product: NC1CCCN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C

Procedure:
To a solution of 4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester (3.3 g, 11.37 mmol) in methanol (50 mL) was added triethylamine (5 mL) and 1,3-propanedithiol (3.42 mL, 35 mmol). The mixture was stirred at ambient temperature until TLC analysis showed complete consumption of the starting material. A white precipitate was removed by filtration and the filtrate was evaporated to dryness. The residue was triturated with a 1:1 hexane/diethyl ether mixture to remove excess dithiol and dried under vacuum to yield 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CCN(C(C)C)C(C)C>[Br:7][C:4]1[S:3][C:2]([N:12]2[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]2)=[N:6][CH:5]=1
Reactant: CN1CCNCC1
Reactant: Brc1cnc(Br)s1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ncc(Br)s2)CC1
Temperature: 110 °C

Procedure:
A solution of 2,5-dibromothiazole (1.000 g, 4.116 mmol) in DIPEA (3.00 mL) was charged with 1-methylpiperazine (0.457 mL, 4.12 mmol) and heated to 110° C. for 3 h then an additional 48 h at rt. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 5% EtOAc in CHCl3→20% EtOAc in CHCl3] resulting in the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=2.34 (s, 3H), 2.48-2.56 (m, 4H), 3.42-3.51 (m, 4H), 7.07 (s, 1H). MS (ES+): m/z=262.09/264.06 (51/49) [MH+]. HPLC: tR=1.57 & 0.53 min (peak splitting; ZQ2, polar—5 min).
Reaction SMILES: C([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[C@H:16]([CH2:27][CH:28](CC1C=CC=CC=1)[C:29](=[O:31])[OH:30])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H].C(OCC)(=O)C>CO.[C].[Pd].O>[C:21]1([S:18]([NH:17][C@H:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:40])=[O:8])=[O:39])[CH2:27][CH2:28][C:29](=[O:30])[OH:31])(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C(Cc1ccccc1)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CC[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 76.9 %

Procedure:
N-benzenesulfonyl-γbenzyl-L-glutamyl-L-proline benzylester (2.61 g, 4.6 mmole) was dissolved in methanol (40 ml), and water (5 ml) suspension of sodium bicarbonate (0.84 g, 10 mmole) was added thereto. Hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 4 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure, and the residue thus obtained was dissolved in water (30 ml). The mixture was washed with two 30 ml portions of diethyl ether, to the water layer 1N aqueous hydrochloric acid (15 ml) was added, and the solution thus obtained was concentrated under reduced pressure. The white residue thus obtained was dispersed in a mixture (100 ml) of ethyl acetate and methanol (1:1), and the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain white solid. It was recrystallized from methanol, ethyl acetate and petroleum ether to obtain N-benzenesulfonyl-L-glutamyl-L-proline (yield: 1.36 g, 76.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:30]([CH:32]([CH3:34])[CH3:33])#[C-:31]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:31]([NH:30][CH:32]([CH3:34])[CH3:33])=[C:13]([C:12]3[CH:15]=[CH:16][CH:17]=[C:10]([Cl:9])[CH:11]=3)[N:8]=2)[CH:7]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: [C-]#[N+]C(C)C
Reactant: Nc1ccc(Cl)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)Nc1c(-c2cccc(Cl)c2)nc2ccc(Cl)cn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 14.8 %

Procedure:
5-Chloropyridin-2-amine (130 mg, 1.01 mmol), 3-chlorobenzaldehyde (171 mg, 1.21 mmol) and p-toluenesulfonic acid monohydrate (77 mg, 0.40 mmol) were combined in 2 mL of methanol to give a clear solution. To this solution was added 2-isocyanopropane (78 mg, 1.13 mmol) and the resulting clear solution was stirred at room temperature for 45 minutes. The mixture was filtered and the white solid was rinsed with methanol three times. The white solid was dried to afford [6-chloro-2-(3-chloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-isopropyl-amine (48 mg, 15%). MS: 320.0 and 322.0 [M+H]+; 1H-NMR (DMSO-d6): δ 8.53 (s, 1H), 8.23 (s, 1H), 8.13 (d, 1H), 7.52 (d, 1H), 7.46 (t, 1H), 7.32 (d, 1H), 7.20 (d, 1H), 4.92 (d, 1H), 3.20 (m, 1H), 1.04 (d, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:37](=[O:46])[C:38]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]2[C:40]1=[O:41])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 21.8 %

Procedure:
In 100 ml of acetonitrile are dissolved 2.0 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 3.0 g of ethyl 2-bromo-9-phthalimidononanoate, and 0.85 g of triethylamine is added to the solution. The mixture is heated at 80° C. for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=3:1 - 2:1) to give from the first fraction 0.9 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22](SN=C=O)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.[CH3:29][N:30](C)C=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:29]([NH:30][C:22]3[CH:21]=[CH:20][C:19]([O:18][C:15]4[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=4)=[CH:24][CH:23]=3)[NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CN(C)C=O
Reactant: O=C=NSc1ccc(Oc2ccncc2)cc1
Product: O=[N+]([O-])c1ccc2nc(Nc3ccc(Oc4ccncc4)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
For further reaction, 1006 mg of 4-nitro-1,2-phenylenediamine and 150 mg of the thioisocyanate 3 prepared are dissolved in 5 ml of dimethylformamide and stirred overnight at room temperature. After removal of the solvent, the residue was purified by MPLC chromatography (Rp 18), giving 126 mg of benzimidazolamine 4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[O:11][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: NC(=O)COCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2coc(COCc3ccccc3)n2)cc1
Temperature: 130 °C
Yield: 42.9 %

Procedure:
To a solution of 2-Benzyloxy-acetamide (1.40 g, 8.56 mmol) in 4 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (2.0 g, 8.56 mmol) and the reaction mixture was heated at 130° C. for 6 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (1.1 g, 44%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:14][C:13]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[OH:11])[O:18][CH2:19][CH:20]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])[CH3:21])=[O:25]
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)Cc1cc(OCC(C)=O)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1cc(OCC(C)NCC(O)c2ccccc2)ccc1O
Yield: 3.7 %

Procedure:
Following a procedure similar to that described in Example 6, but using 0.72 g of 2-amino-1-phenylethanol, 1.5 g of methyl 2-hydroxy-5-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 21), 60 ml of benzene, 50 ml of absolute methanol and 1.9 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, 0.07 g of the title compound was obtained having an Rf=0.40 (thin layer chromatography over silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]([C:15]4[C:19]5=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]5[N:17]([CH3:28])[CH:16]=4)=[CH:14][C:7]=23)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O.ClCCl>[CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13]([C:15]4[C:19]5=[N:20][C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=[C:18]5[N:17]([CH3:28])[CH:16]=4)=[CH:14][C:7]=23)[CH2:2][CH2:3]1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CC4)ccnc3[nH]1)cn2C
Yield: 96 %

Procedure:
To a solution of 0.11 g of cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine in 20 cm3 of methanol, at a temperature in the region of 20° C., is added 1 cm3 of 5N potassium hydroxide. The reaction medium is refluxed for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 20 cm3 of water. The solid formed is filtered off on a sinter funnel. The solid obtained is taken up in 80 cm3 of dichloromethane and 3 cm3 of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give 0.075 g of cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine with the following characteristics:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:19]=2)[CH:3]=1.[C:33]1([SH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[C:27]1([C@@H:25]([NH:24][C:20]2[N:19]=[C:18]([C:4]3[CH:3]=[C:2]([S:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:7]=[N:6][C:5]=3[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:23]=[CH:22][N:21]=2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Sc1ccccc1
Reactant: C[C@H](Nc1nccc(-c2cc(Cl)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nccc(-c2cc(Sc3ccccc3)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 120 °C
Yield: 51 %

Procedure:
Compound 10 (100 mg, 0.220 mmol), thiophenol (˜200 μL), and diisopropylethylamine (100 mL) were combined under Ar and heated at 120° C. for 3 h. The mixture was purified by flash column chromatography (hexane:ethyl acetate 70:30) to afford a foam. Crystallization from hexane:ethyl acetate afforded 59 mg (0.112 mmol, 51%) of Compound 86.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:23](O)(=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>O1CCCC1.C(Cl)Cl>[CH2:24]([C:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCc1ccc2nc(-c3ccc(O)cc3)sc2c1
Reactant: CCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCC(=O)Oc1ccc(-c2nc3ccc(CCCCCC)cc3s2)cc1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To 0.32 g (1.03 mM) of 2-(p-hydroxyphenyl)-6-hexylbenzothiazole, 0.13 g 1.03 mM) of heptanoic acid, 15 ml of methylene chloride and 5 ml of tetrahydrofuran were added, followed by addition of 0.21 g of N,N'-dicyclohexylcarbodiimide (DCC) and 0.02 g of 4-pyrrolidinopyridine under stirring at room temperature and further stirring for 6 hours at room temperature. After the reaction, the resultant N,N'-dicyclohexylurea was recovered by filtration, followed by washing with methylene chloride to be added to the filtrate. The solvent of the resultant filtrate was distilled-off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene), followed by two times of recrystallization from a mixture solvent of toluene/methanol to obtain 0.39 g of 2-(p-hexylcarbonyloxyphenyl)-6-hexylbenzothiazole (Yield: 88.6%). ##STR203##
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(OC(OCC)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=1)C.O>C(O)CCC.Cl>[ClH:1].[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:17]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:20][CH:21]=1)[CH:27]=[CH2:28]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: C=CCOc1ccc(OCC(OCC)OCC)cc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: C=CCOc1ccc(OC2NCCc3cc(O)c(O)cc32)cc1
Yield: 98.6 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (3.3 g) and (4-allyloxyphenoxy)acetaldehyde diethyl acetal (5.2 g) in a mixture of n-butanol (45 ml), water (12 ml) and concentrated hydrochloric acid (2 drops) was refluxed for 4 hours. After the reaction, the reaction mixture was concentrated to dryness. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of 99% ethanol and ether to give 1-(4-allyloxyphenoxy)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g), mp 114° to 116°C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].CN(C)CCO.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:9](=[O:10])([O:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: C[C@H](O)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of (S)-(−)-1,1,1-trifluoro-2-propanol (1.95 g) in CHCl3 (30 mL) was added 4-nitrophenyl chloroformate (5.16 g) and pyridine (1.35 g) at room temperature. After 1-hour stirring at 60° C., the resulting mixture was cooled to room temperature. To the resulting mixture was added 2-(dimethylamino)ethanol (1.52 g) and was stirred at room temperature for 1 hour. The mixture was poured into 1M aqueous solution of HCl and extracted with CHCl3. The extract was washed with water and then dried over Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=[N:19][OH:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[N:29]1C(=O)CC[C:30]1=O.CN.C(N(CC)CC)C>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:19][OH:20])=[N:29][CH3:30])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Agent: CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN=C(NO)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 75 °C
Yield: 39 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde oxime (i.e. the product of Step 2, 500 mg) in DMF (25 mL) was added N-chloro succinimide (168 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto water and extracted with MTBE. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of methylamine (0.66 mL, 41 mg) and triethylamine (0.18 mL, 0.13 g) in THF and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (270 mg, 39%) as a colorless solid.