Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1.[NH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.[Cl-].C(N(C(C)C)CC)(C)C>C(O)C>[OH:1][C@@H:2]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1)[CH2:3][N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Reactant: O=C1CCNCC1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCC(=O)CC3)ccc2s1

Procedure:
To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (2.0 g, 9.25 mmol) and piperidin-4-one, chloride (1.25 g, 9.25 mmol) in ethanol was added diisopropylethylamine (1.6 ml, 9.0 mmol). The mixture was heated to reflux for 16 hours. The solvent was removed and the residue purified by column chromatography (10:1 DCM:MeOH) followed by preparative TLC (10:1 DCM:MeOH) to yield 1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-one.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH2:34][C@@H:35]([CH2:44][OH:45])[C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[OH:37][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:35]([NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)=[O:18])[CH2:44][OH:45]
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)N[C@@H](CO)[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound was obtained in 93% purity by HPLC. MS(ESI+): m/z=489.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[C:10]([CH3:48])=[C:11]([CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)[C:12]([O:33][CH3:34])=[C:13]([CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3C2CCCCO2)[CH3:16])[CH:14]=1.C(Cl)[Cl:50]>>[Cl:8][C:9]1[C:10]([CH3:48])=[C:11]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:12]([O:33][CH3:34])=[C:13]([CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH:14]=1.[ClH:50]
Reactant: ClCCl
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.0 M HCl in dioxane (2.0 mL, 8 mmol) was added to a solution of tert-butyl 4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]piperidine-1-carboxylate (250 mg, 0.43 mmol) in methylene chloride (1.0 mL, 16 mmol) and the reaction was stirred at room temperature for 1 hour. The solvent was removed to provide the desired product as HCl salt which was used in the next step without further purification. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2. found: =401.2.
Reaction SMILES: [CH2:1]([C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[C:10](=[O:37])[CH2:11][CH2:12][NH:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=2[Cl:23])[N:16](C(OC(C)(C)C)=O)[C:15]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[C:10](=[O:37])[CH2:11][CH2:12][NH:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:24])=[CH:20][C:21]=2[Cl:23])[NH:16][C:15]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2Cc2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1Cc1ccccc1

Procedure:
Dissolve 3-[(2-benzylphenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (320 mg, 0.55 mmol) in methylene chloride (5 mL). Add trifluoroacetic acid (1 mL) and stir at room temperature for 3 hours. Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) togive the title compound (250 mg, 95%); mp 208°-209° C.
Reaction SMILES: [Cl:1]CCCC[CH:6]1[O:10][C:9](=[O:11])[N:8]([CH:12]([CH3:14])[CH3:13])[CH2:7]1.Cl.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:17].[I-].[K+].Cl>C(O)C.CCOCC>[ClH:1].[CH2:16]([O:18][C:19]1[CH:21]=[CH:20][CH:19]=[CH:24][C:24]=1[CH2:23][CH2:22][CH2:21][CH:20]([CH:7]1[CH2:6][O:10][C:9](=[O:11])[N:8]1[CH:12]([CH3:13])[CH3:14])[N:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1)[CH3:17]
Reactant: CC(C)N1CC(CCCCCl)OC1=O
Reactant: CCOc1ccccc1N1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOc1ccccc1CCCC(C1COC(=O)N1C(C)C)N1CCNCC1
Yield: 60 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-(1-methylethyl)-2-oxazolidinone (5.2 g, 0.0137 mol), 1-(2-ethoxyphenyl)-piperazine hydrochloride (5.76 g, 0.0237 mol) and potassium iodide (1.0 g) in N-butanol (200 mL) gave an oil. The oil was dissolved in absolute ethanol and acidified with ethanolic hydrogen chloride. Addition of ether and filtration gave a solid which was dried under high vacuum at 70° C. to give 6.62 g (60% yield), mp 199°-205° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2].[CH3:19][NH:20][CH3:21].C(O)(=O)C.[BH3-]C#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH2:15][N:20]([CH3:21])[CH3:19])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)oc2ccc(C=O)cc12
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)oc2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (5-formyl-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (1.00 g, 4.06 mmol) in anhydrous ethanol (25 mL) is added a 5 M solution of dimethylamine in ethanol (4.1 mL). The resulting reaction mixture is stirred for 18 h at room temperature. Acetic acid (1.4 mL) and NaBH3CN (279 mg, 4.22 mmol) are added and the resulting reaction mixture is heated at 50° C. for 4 h. After cooling to room temperature the solvents are removed by rotary evaporation. The residue is taken up in water, basified (pH=8) with a saturated aqueous NaHCO3 solution and extracted twice with EtOAc. The combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, gradient of dichloromethane/methanol 10:0 to 9:1) to afford the title compound as a colorless oil (744 mg, 2.70 mmol, 67%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.39 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.58 (s, 2H), 3.50 (s, 2H), 2.41 (s, 3H), 2.25 (s, 6H), 1.23 (t, J=7.1 Hz, 3H). MS (ES+): 276 (M(C16H21NO3)+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:19])[C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:26]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.N>C1COCC1.O>[NH2:26][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:19]
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylbutanoic acid (6.5 g, 23.27 mmol) in THF (60 mL) was added HOBT (3.00 g, 19.60 mmol), EDCI (3.76 g, 19.60 mmol) and DIPEA (10.27 ml, 58.8 mmol) and stirred at 0° C. for 30 min. 3M ammonia in THF (50 ml, 1848 mmol) was added to afford a white suspension. The reaction mixture was allowed to stir for 12 h at RT. Reaction mass was diluted with water (80 ml). The aqueous layer was treated with EtOAC (3×80 ml). The organic layer was dried over Na2SO4 and concentrated under vacuum to get desired crude product. Crude product was purified by column chromatography (60-120 mesh, 30% EtOAc: Pet-Ether) to get desired product as off white solid (2.7 g, 52%). 1HNMR (400 MHz, CDCl3) δ ppm: 1.15-1.17 (d, J=6.8 Hz, 3H), 1.23-1.27 (m, 6H), 3.66-3.76 (m, 1H), 5.10-5.13 (s, 2H), 5.41-5.89 (m, 3H), 7.26-7.36 (m, 5H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].C(=O)(O)[O-].[Na+]>CCOCC>[CH:7]1[C:6]([C:4]([CH2:3][Br:1])=[O:5])=[CH:11][CH:10]=[C:9]([OH:12])[CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1ccc(O)cc1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
Bromine (17.6 g, 110 mmol) was added dropwise to a 0° C. solution of 4-hydroxyacetophenone (15 g, 110 mmol) in ether (200 mL) over 20 minutes. The mixture was stirred for 1 hour and poured carefully into saturated sodium bicarbonate solution (500 mL). The organics were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The crude product was then recrystallized from ether to afford the title compound (14.1 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:22]([O:29][C:30]([N:13]1[CH2:12][CH2:11][N:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:15][CH2:14]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCN(c2ncccc2[N+](=O)[O-])CC1
Reaction time: 1.5 h

Procedure:
1-(3-Nitro-2-pyridinyl)piperazine is dissolved in 175 ml of methylene chloride and cooled to 0°. Then pyridine is added followed by benzylchloroformate (16.5 ml). The reaction is stirred 1.5 hr, then poured into saturated aqueous sodium bicarbonate and extracted with chloroform, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound, NMR (300 MHz, CDCl3) 8.34, 8.15, 7.38-7.32, 6.81, 5.17, 3.65 and 3.45 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](=O)[CH2:27][C:28](=O)[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:28]([CH3:29])=[CH:27][C:26]([C:22]4[O:21][CH:25]=[CH:24][CH:23]=4)=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)c1ccco1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Product: Cc1cc(-c2ccco2)nn1-c1nc(Nc2ccc(Cl)cc2)c2ncn(C)c2n1

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 1-(2-furyl)-1,3-butanedione.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][N:7]=1)=[O:4].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21](=[O:34])[C:22]([OH:33])([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:13]2>C(Cl)(Cl)Cl.C(#N)C>[Br-:1].[OH:33][C:22]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:21]([O:20][C@@H:14]1[CH:15]2[CH2:18][CH2:19][N+:12]([CH2:2][C:3](=[O:4])[NH:5][C:6]3[CH:11]=[CH:10][N:9]=[CH:8][N:7]=3)([CH2:17][CH2:16]2)[CH2:13]1)=[O:34]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)c1cccs1
Reactant: O=C(CBr)Nc1ccncn1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2)Nc1ccncn1
Product: [Br-]
Temperature: 25 °C

Procedure:
A solution of 2-Bromo-N-pyrimidin-4-yl-acetamide (0.90 g, 4.17 mmol) and hydroxy-di-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 70(ii)) (1.32 g, 3.79 mmol) in dry chloroform-acetonitrile (20 ml+4 ml) are heated at 50° C. for 3 hours. The mixture is then cooled to room temperature and concentrated. Purification by reverse phase C18 column chromatography (gradient elution 100% water to 100% acetonitrile) gives after concentration a light brown solid. The solid was triturated with hot acetonitrile then dissolved in hot acetonitrile containing a few drops of water. After standing at 5° C. for several hours crystals are formed which are filtered and dried to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12](O)=O)=[CH:8][NH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1.CN(C)[CH:24]=[O:25]>>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([CH2:12][C:24]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:25])=[CH:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(=O)c(C(=O)O)c[nH]c2n1
Reactant: CN(C)C=O
Reactant: Nc1nnn[nH]1
Product: Cc1ccc2c(=O)c(CC(=O)Nc3nnn[nH]3)c[nH]c2n1

Procedure:
1,4-Dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (4 g) and N,N'-carbonyldiimidazole (3.5 g) in dimethylformamide (40 ml) were heated at 80° for 6 hours. 5-Amino-1H-tetrazole (2.5 g) was added and the mixture was stirred and heated at 80° for 1.5 hours. The solid was collected and dissolved in aqueous sodium hydroxide. The solution was acidified with glacial acetic acid and the solid was collected and dried. It had m.p. 344°-345.5°, (47%)
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1.[CH:28]1[C:33]2[NH:34][CH2:35][CH2:36][CH2:37][O:38][C:32]=2[CH:31]=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:28]1[C:33]2[N:34]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][CH2:12][C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:26])[CH3:27])[CH2:10][CH2:9]4)=[O:25])=[C:16]([CH3:24])[CH:17]=3)=[O:21])[CH2:35][CH2:36][CH2:37][O:38][C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc2c(c1)NCCCO2
Reactant: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCCOc3ccccc32)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Yield: 10 %

Procedure:
WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (55 mg, 0.15 mmol) and 6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (44 mg, 0.30 mmol) in di-chloromethane (3 ml) and DIEA (0.052 ml, 0.30 mmol). The mixture was heated at reflux for 5 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white solid identified as the title compound (6 mg, 10%).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:52]([C:51]3[CH:55]=[CH:56][C:48]([Cl:47])=[CH:49][CH:50]=3)=[O:53])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.210 g, 0.35 mmol) in pyridine (2 mL) was added 4-chlorobenzoyl chloride (0.051 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.090 g, 62% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.45 (br s, 1H), 10.54 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.10 (d, 1H), 8.04 (d, 2H), 7.93 (d, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.64 (d, 2H), 7.56 (t, 1H); ES-MS (m/z) 415 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([CH3:29])[C:18]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:27])[Cl:28])[CH:20]=[C:19]([CH3:29])[C:18]=1[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:8][N:7]=1
Reactant: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 0.33 g of 2-(3-hydroxypropyloxy)-5-trifluoromethylpyridine, 0.40 g of 2-chloro-6-methyl-4-(3,3-dichloro-2-propenyloxy)phenol and 0.41 g of triphenylphosphine dissolved in 30 ml of dichloromethane was added dropwise a solution of 0.32 g of diisopropyl azodicarboxylate dissolved in 3 ml of dichloromethane, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.56 g of 3-chloro-5-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (92% yield), nD23.6 1.5294.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:3]=1OC(=O)CCCC.[OH-:29].[Na+].[CH3:31][OH:32]>>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH:1]([CH2:2][CH2:3][CH3:4])[C:31]([OH:32])=[O:29]
Reactant: CCCCC(=O)Oc1c(C)nc2sc3c(c2c1-c1cccc(C)c1)CCCC3
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1cccc(C)c1)CCCC3
Temperature: 60 °C
Yield: 52 %

Procedure:
To a solution of methyl [[2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.281 g; 0.65 mmol) in methanol (6.5 mL) was added a solution of sodium hydroxide 5 N (1.3 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.129 g (52%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCc1ccc(N=Nc2ccc(OC)cc2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
All chemicals were obtained from Sigma-Aldrich Chemical Co. unless otherwise noted. One eq. of 4-butyl-4′-hydroxyazobenzene (obtained from Beam Corp.) and 1.1 eq. potassium carbonate were dissolved in acetone and degassed with argon. Iodomethane (2.5 eq) in acetone was degassed and added drop-wise to the stirred mixture. The mixture was heated to 45° C. and stirred overnight. The progress of the reaction was monitored by thin-layer chromatography (TLC); 12 h was usually sufficient for complete methylation. The hot reaction mixture was then filtered to remove the precipitated potassium iodide. The filtrate was collected and the solvent removed in vacuo. The solid residue was re-dissolved in chloroform and then insoluble salts were removed by filtration. The filtrate was washed with water, and the organic layer was separated and dried over magnesium sulfate. Removing the solvent in vacuo afforded a solid that contained the desired product (“BMAB”) containing a small amount of un-reacted starting material 4-butyl-4′-hydroxyazobenzene. Recrystallization from methanol at −68° C. afforded pure crystals of BMAB that were collected by filtration. (K 35 N 45 I) 1H NMR 200 MHz δ ppm=0.94 (t, 3H), 1.18 (q, 2H), 1.66 (q, 2H), 2.66 (t, 2H), 3.86 (s, 2H), 7.0 (d, 2H), 7.26 (d, 2H), 7.82 (d, 2H), 7.88 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[CH2:48]([N:55]1[CH2:60][CH2:59][O:58][C@@H:57]([CH2:61][NH2:62])[CH2:56]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O>[CH2:48]([N:55]1[CH2:60][CH2:59][O:58][C@@H:57]([CH2:61][NH:62][C:14](=[O:16])[CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])[CH2:56]1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: NC[C@H]1CN(Cc2ccccc2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccccc2)nc1CC(=O)NC[C@H]1CN(Cc2ccccc2)CCO1
Reaction time: 0.08 h
Yield: 104.4 %

Procedure:
A mixture of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (0.263 g), 1-hydroxylbenzotriazole (0.163 g), and N,N-diisopropylethylamine (0.211 ml) in N,N-dimethylformamide (3 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.232 g). The mixture was stirred for 5 min, treated with 1-[(2S)-4-benzylmorpholin-2-yl]methanamine (prepared in accordance with EP 0 995 746 A1; 0.192 g), and the solution was stirred at 22° C. for 18 h. The mixture was partitioned between dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The phases were separated in a hydrophobic frit; the organic phase was loaded onto a solid phase extraction cartridge (10 g SCX) and eluted with methanol, followed by 0.880 ammonia:methanol 10:90 to give the title compound as a colourless gum (0.394 g).