Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([OH:19])=O)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.CC(C)(OC([N:38]1[C@H:46]([C:47]([O:49][CH2:50][O:51][C:52](=[O:57])[C:53]([CH3:56])([CH3:55])[CH3:54])=[O:48])[CH2:45][C:40]2([S:44][CH2:43][CH2:42][S:41]2)[CH2:39]1)=O)C.FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([CH:43]1[CH2:42][S:41][C:40]2([CH2:45][CH:46]([C:47]([O:49][CH2:50][O:51][C:52](=[O:57])[C:53]([CH3:55])([CH3:54])[CH3:56])=[O:48])[NH:38][CH2:39]2)[S:44]1)=[O:19])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(C[C@H]1C(=O)OCOC(=O)C(C)(C)C)SCCS2
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)C1CSC2(CNC(C(=O)OCOC(=O)C(C)(C)C)C2)S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A mixture of 1.7 g of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid, acetonitrile and 0.96 g of carbonyldiimidazole is stirred under argon at 0° C. for 1 hour. (S)-7-[(1,1-Dimethylethoxy)carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester (2.5 g) is treated with trifluoroacetic acid (about 2 ml) and stirred at room temperature for 30 minutes. The trifluoroacetic acid is removed in vacuo, the residue taken up in acetonitrile and added dropwise to the above mixture over a 20 minute period at room temperature. After an additional 2.5 hours, the acetonitrile is stripped and the resulting oil is partitioned between ethyl acetate and water. The layers are separated and the organic portion is washed with 5% potassium sulfate, saturated sodium bicarbonate, brine, dried (MgSO4) and evaporated. The residue (3.4 g) is chromatographed on silica (120 g) eluting with ethyl acetate/dichloromethane (1:1) and yielding 2.7 g of the title compound as a glass.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1>>[CH3:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[N:14]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(-n2cc(C)ccc2=O)cc1
Yield: 89 %

Procedure:
The reaction of p-iodotoluene with 5-methyl-2-(1H)-pyridone by the procedure of Example 1, affords 5-Methyl-1-p-tolyl-2-(1H)-pyridone in 89% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C@@H:12]3[C@@H:8]([CH2:9][C:10](=[O:19])[NH:11]3)[CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27](=O)([O:33]C(C)(C)C)[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>ClCCl>[O:19]=[C:10]1[CH2:9][C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]3([CH2:7]2)[CH2:3][CH2:2][N:1]([C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[CH2:6][CH2:5]3)[NH:11]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1C[C@H]2CC3(CCNCC3)c3ccccc3[C@H]2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H]1CC(=O)N[C@@H]1c1ccccc12
Yield: 55.9 %

Procedure:
A solution of the (3aR,9bS)-1,3a,4,9b-tetrahydrospiro[benzo[g]indole-5,4′-piperidin]-2(3H)-one (900 mg, 3.51 mmol) in dichloromethane (100 ml) was treated with triethylamine (3 ml) and di-tert-butyl carbonate (1.5 g, 6.8 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane, washed with aqueous saturated NH4Cl. The organic phase was separated and the aqueous phase was re-extracted with dichloromethane (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by flasj chromatography (40 g silica gel, CH2Cl2/CH3CN up to 0:100%) to give (3aR,9bS)-tert-butyl 2-oxo-1,2,3,3a,4,9b-hexahydrospiro[benzo[g]indole-5,4′-piperidine]-1′-carboxylate 12 (700 mg). LC-MS: m/e=301.5 (M−t-Bu+H, 100%). Rt=3.04 min. 1H NMR (300 MHz, CDCl3): 7.36 (d, 1H), 7.25 (td, 1H), 7.21-7.13 (m, 2H), 6.32 (s, 1H, NH), 4.71 (d, J=5.8 Hz, 1H, CHN), 4.02 (br. d, 1H), 3.90 (br. d, 1H), 3.01 (td, J=13.4, 2.8 Hz, 1H), 2.89 (td, J=13, 3.1 Hz, 1H), 2.73-2.62 (m, 1H), 2.29 (td, J=12.7, 5.0 Hz, 1H), 2.23-2.44 (m, 3H), 1.66-1.59 (m, 1H), 1.51 (dd, J=13.2, 4.3 Hz, 1H), 1.41 (s, 9H), 1.37-1.30 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]Br>C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Yield: 103.3 %

Procedure:
4-methylbenzophenone (10.0 g; 51.0 mmol) was dissolved in benzene (60 mL) and the solution was warmed to reflux. Solution of bromine (8.39 g; 52.5 mmol) in benzene (15 mL) was added to the reaction mixture over 10 h. The reaction was refluxed for a further 6 h until a light orange solution in obtained and all bromine is consumed. The benzene solvent was evaporated and crude product was obtained as an off-white solid. Recrystallisation from methanol (130 mL) provided 4-(bromomethyl)benzophenone (14.5 g; 69% yield) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].CO[CH2:11][N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:7][O:6][C:4]([C:3]1([O:2][CH3:1])[CH2:8][CH2:11][N:12]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13]1)=[O:5]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(OC)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(OC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a stirred solution of methyl 2-methoxyacrylate (20.8 g, 179 mmols) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (55 ml, 215 mmols) in dichloromethane (160 ml) was added at 0° C. a solution of trifluoroacetic acid (2 ml) in dichloromethane (10 ml). The resulting solution was warmed to room temperature and stirred overnight. After concentration, the crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate/hexanes/Et3N (1000:3000:4 to 1000:1000:3) to give the title compound (10BH) (17.7 mg, 40%). (Note: adding Et3N is essential to ensure sharp separation.)
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]([NH:22]N)[CH:18]=[C:19]([CH3:21])[CH:20]=1.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]([CH3:27])=O.O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:30]([O:29][C:24]([C:25]1[NH:22][C:17]2[C:16]([CH:27]=1)=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=2)=[O:28])[CH3:31]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1cc(C)cc(NN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1cc2c(C)cc(C)cc2[nH]1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
In a flask fitted with a Dean-Stark trap, p-toluenesulfonic acid monohydrate (132 g, 0.69 mol) in 500 ml of benzene was heated at reflux for 2 hours. A solution of 3,5-dimethylphenylhydrazine hydrochloride (34.5 g, 0.2 mol), ethyl pyruvate (23.2 g, 0.2 mol), and p-toluenesulfonic acid monohydrate (0.85 g, 0.005 mol) in 500 ml of benzene, which had been refluxed for 2 hours with water removed through a Dean-Stark apparatus was then added. The resulting mixture was heated at reflux and stirred overnight. After cooling, the solution was treated with saturated sodium bicarbonate solution and diluted with methylene chloride. The organic portion was washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by ISCO (hexane/EtOAc, 0-30%, 40 min) to give yellow solids, which was recrystallized from hexane/ethyl acetate (10%) to give colorless needles (35.6 g, 82%). 1H NMR (DMSO-d6, 400 MHz): δ 11.68 (brs, 1H, exchangeable with D2O, NH), 7.12 (s, 1H), 7.05 (s, 1H), 6.71 (s, 1H), 4.33 (q, J=6.8 Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 1.34 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CCN=C=NCCCN(C)C.Cl.[CH:34](O)=[O:35]>C1COCC1.O>[CH:34]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:6]=2)[CH2:1]1)=[O:35]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C=O)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 73.4 %

Procedure:
A solution of N-[[(5S)-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 1, Step 6, 200 mg, 0.691 mmol) in THF is treated with EDC.HCl (172 mg, 0.899 mmol) and formic acid (34 μL, 0.899 mmol) to give a white slurry which is then diluted with H2O (approx. 2 mL) to give a homogeneous mixture. The mixture is stirred at ambient temperature for 1.25 hrs and is then diluted with H2O (10 mL) and extracted with CH2Cl2 (4×20 mL). The combined organic phase is washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-5/95). Those fractions with an Rf=0.41 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated and the resulting glassy solid is triturated with Et2O and filtered to give 161 mg (74%) of the title compound as a white solid, mp 139-141° C. (dec.). [α]25D=−22° (c 0.92, DMSO).
Reaction SMILES: [N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27]C(CNC)=[CH:25][CH:24]=1.Cl.N1CCC1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:3]([CH2:4][N:1]([CH3:2])[C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)=[CH:25][CH:24]=1
Reactant: Cc1nc(-c2cnn(C)c2)c2c(N3CCC3)ncnn12
Reactant: CNCc1ccc(OC)cc1
Agent: C1CNC1
Agent: Cl
Product: COc1ccc(CN(C)c2ncnn3c(C)nc(-c4cnn(C)c4)c23)cc1

Procedure:
The product was synthesized in a manner similar to that described for the preparation of 4-(azetidin-1-yl)-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazine in Example 2, except that 1-(4-methoxyphenyl)-N-methylmethanamine was utilized in place of azetidine hydrochloride, and the workup was modified somewhat: after the slurry was extracted with dichloromethane, the combined organic layers were washed with 1 N aqueous sodium hydroxide solution, washed with saturated aqueous sodium chloride solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and passed through a short column of silica gel (Eluant: 5% methanol in ethyl acetate). The eluant was concentrated under reduced pressure, and the resulting solid was washed with tert-butyl methyl ether followed by diethyl ether, to provide C6. Yield: 36.0 g, 99.1 mmol, 76%. LCMS m/z 364.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.67 (s, 3H), 2.84 (s, 3H), 3.77 (s, 3H), 3.88 (s, 3H), 4.66 (s, 2H), 6.82 (br d, J=8.7 Hz, 2H), 7.07 (br d, J=8.6 Hz, 2H), 7.58 (s, 1H), 7.62 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC(CC)CC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CCC(CC)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCC(CC)Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 15.1 %

Procedure:
The title compound (0.010 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 1-bromo-2-ethyl-butane (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-ethyl-butyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C19H26ClN3, 331.18; found, m/z 332.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.50-7.48 (br m, 4H), 4.11-4.09 (br m, 2H), 3.71-3.69 (br m, 2H), 3.33-3.31 (br m, 2H), 3.26-3.24 (br m, 2H), 3.06-3.04 (br m, 2H), 1.91-1.89 (m, 1H), 1.36-1.34 (m, 4H), 0.93 (t, J=7.3 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:42]1[CH2:48][CH2:47][CH2:46][C@H:43]1[CH2:44][OH:45]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([N:42]1[CH2:48][CH2:47][CH2:46][C@H:43]1[CH:44]=[O:45])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 22.1 g of N-benzyloxycarbonyl-proline. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 450 ml of THF. To this solution was added 8.2 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant white solid substance were added 40.5 g of WSCD.HCl and 150 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 6.3 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 350 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 200 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 200 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 3.4 g (10.3%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[OH:11][C:12]1[CH:13]=[CH:14][C:15]2[C:19]([C:20]([O-:22])=[O:21])=[C:18]([CH3:23])[S:17][C:16]=2[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:23][C:18]1[S:17][C:16]2[CH:24]=[C:12]([O:11][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)[CH:13]=[CH:14][C:15]=2[C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Clc1ccnc2ccsc12
Reactant: Cc1sc2cc(O)ccc2c1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Yield: 27.2 %

Procedure:
This material was prepared by reacting 7-chlorothieno[3,2-b]pyridine (170 mg, 1.0 mmole) with methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (267 mg, 1.2 mmole) and Cs2CO3 (488 mg, 1.5 mmole) in a manner similar to that previously described for example 1. Silica gel chromatography (10% MeOH/CHCl2) provided the title compound as a brown viscous oil (93 mg, 27%) of. 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (1H, d, J=5.27 Hz), 8.41 (1H, d, J=8.85 Hz), 8.11 (1H, d, J=5.46 Hz), 7.93 (1H, d, J=2.07 Hz), 7.55 (1H, d, J=7.55 Hz), 7.32 (1H, dd, J=2.26, 8.85 Hz), 6.64 (1H, d, J=5.27 Hz), 2.77 (3H, s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=S)=[CH:38][C:30]=1[O:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1>CC#N.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][C:43]([NH:42][C:39]5[CH:40]=[CH:41][C:29]([Cl:28])=[C:30]([O:31][CH2:32][CH:33]6[CH2:37][CH2:36][CH2:35][O:34]6)[CH:38]=5)=[N:27][C:22]=4[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=Nc1ccc(Cl)c(OCC2CCCO2)c1
Reactant: Nc1cc(Oc2ccnc(C(=O)NCCCCN3CCCC3)c2)ccc1O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc3oc(Nc4ccc(Cl)c(OCC5CCCO5)c4)nc3c2)ccn1

Procedure:
To a stirring RT solution of 4-(3-amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Step E, 162 mg, 0.438 mmol) in CH3CN (20 mL) and DMF (2 mL) was added 2-(2-chloro-5-isothiocyanato-phenoxymethyl)-tetrahydro-furan (112 mg, 0.417 mmol). The following day, the CH3CN was evaporated off, and the crude mix was diluted into 1 N NaOH and EtOAc. The layers were separated. The aqueous layer was extracted 3× with EtOAc, and the combined organic layers were washed once with 1N NaOH and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound as a yellow solid. MS(MH+)=606.3; Calc'd 605.24 for C32H36ClN5O5.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:16][O:17][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(COCc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.8 %

Procedure:
Sodium hydride (60% suspension in oil, 4.9 mg, 0.11 mmol) was added in small portions to a cooled (0° C.) solution of 4-tert-butoxycarbonylamino-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (19 mg, 0.057 mmol) in dry DMF (0.2 mL). The suspension was stirred vigorously at 0° C. for 15 min followed by addition of 4-chlorobenzyl bromide (14 mg, 0.066 mmol). After stirring for 45 min at 0° C., the reaction mixture was warmed to rt. When TLC showed complete consumption of the starting material, the reaction mixture was partioned between ethyl acetate (5 mL) and water (2 mL). The aqueous phase was further extracted with ethyl acetate (5 mL). The combined organic layers were dried (Mg2SO4), filtered and concentrated. Flash column chromatography on silica, eluting with 1% methanol in dichloromethane, gave 4-tert-butoxycarbonylamino-4-(4-chloro-benzyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (6 mg, 0.013 mmol, 22%). LC-MS (LCT2) m/z 477 [M+Na+], Rt 8.74 min.
Reaction SMILES: C1(N2C(=O)C3=CNC4C=CC(N5CCNCC5)=NC=4C3=N2)C=CC=CC=1.F[C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:47])[N:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)[N:40]=[C:31]3[C:30]=2[N:29]=1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.N1CCNCC1>>[N:48]1([C:28]2[CH:37]=[CH:36][C:35]3[NH:34][CH:33]=[C:32]4[C:38](=[O:47])[N:39]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)[N:40]=[C:31]4[C:30]=3[N:29]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccn1
Reactant: C1COCCN1
Agent: C1CNCCN1
Agent: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCOCC4)nc3c-2nn1-c1ccccn1

Procedure:
The title compound was prepared following the procedure described for 6a using 5b and morpholine instead of 5a and piperazine respectively. 1H-NMR (DMSO-d6) δ (ppm): 3.63 (4H, br), 3.72 (4H, br), 7.19 (2H, m), 7.82 (2H, m), 8.22 (1H, d, J=8.24 Hz), 8.48 (1H, dd, J=2.20, 1.10 Hz), 8.56 (1H, s). m/z 349.4 (MH+).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[S:9](=O)(=[O:12])([OH:11])[OH:10].C(=O)([O-])[O-].[Ba+2]>>[OH:2][C:1]1[CH:8]=[C:7]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Product: O=S(=O)(O)c1ccc(O)c(O)c1
Temperature: 45 °C

Procedure:
Catechol (180 g.) was added in portions to stirred sulfuric acid (138.5 ml.) so that the reaction temperature remained below 25° C. After addition was complete, the semi-solid mixture was heated at 45° C. for 60 minutes then cooled to room temperature and poured into ice-water (700 ml.). The solution was neutralized with solid barium carbonate, the barium sulfate collected, the filtrate acidified to pH 1 with concentrated sulfuric acid then refiltered. The filtrate was evaporated to leave crude 3,4-dihydroxybenzenesulfonic acid (182.40 g.) which was used without purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([S:45]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)(=[O:47])=[O:46])=[CH:43][CH:44]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (1.40 g, 3.53 mmol) and triethylamine (1.48 mL, 10.59 mmol) in methylene chloride (35 mL) was added 4-methoxy-benzenesulfonyl chloride (1.46 g, 7.06 mmol) in three portions over 15 minutes. The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with saturated sodium bicarbonate and the aqueous solution was washed with methylene chloride. The combined organic solutions were dried (magnesium sulfate), filtered, and concentrated. Medium pressure chromatography using a solvent gradient (4% to 10% methanol/methylene chloride) afforded the title compound of Step A. MS 483.1 (M+1)+