Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[NH:28][CH:29]=[N:30][C:26]=3[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:33].[BH4-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[NH:28][CH:29]=[N:30][C:26]=3[CH:25]=2)[C:14]([N:16]2[CH2:17][CH2:18][CH:19]([OH:22])[CH2:20][CH2:21]2)=[O:15])(=[O:10])=[O:11])=[CH:4][C:3]=1[Cl:33]
Reactant: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCC(=O)CC2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCC(O)CC2)cc1Cl
Reaction time: 12 h

Procedure:
410 mg (0.8 mMol) of 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(piperidin-4-on-1-yl]-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide are dissolved in 8 ml of absolute dimethylformamide, mixed with 100 mg (2.6 mMol) of sodium borohydride and left to stand for 12 hours at ambient temperature. Then the reaction mixture is poured into water and extracted 3 times with ethyl acetate. The organic phase is washed twice with water, dried with sodium sulphate and evaporated down. The residue is purified over a silica gel column, the evaporated eluate is triturated with ether and suction filtered.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)[S:7][C:6]=1[C:18]([NH2:20])=[O:19])=[O:3].B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[S:7][C:6]=1[C:18]([NH2:20])=[O:19])=[O:3]
Reactant: COc1ccccc1-c1cc(NC(N)=O)c(C(N)=O)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: NC(=O)Nc1cc(-c2ccccc2O)sc1C(N)=O
Reaction time: 1 h

Procedure:
3-[(Aminocarbonyl)amino]-5-(2-methoxyphenyl)-2-thiophenecarboxamide (0.1 g), boron tribromide (2 ml of a 1M solution in dichloromethane) and dichloromethane (10 mL) were stirred at room temperature for 16 h. Methanol (5 mL) was added and after 1 h, the solvent was evaporated. 2M Hydrochloric acid (10 mL) was added and, after stirring for 1 h, the phenol was filtered off and used directly in step (b).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH:33]([CH3:35])[CH3:34])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH:33]([CH3:35])[CH3:34])[N:27]=2)[CH:6]=1
Reactant: Cc1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc(C(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)nc(C(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (35 mg, 72.4 μmol) in dichloromethane (1.1 mL) was added trifluoroacetic acid (165 mg, 112 μL, 1.45 mmol) and the mixture stirred at room temperature for 20 h. The mixture was concentrated in vacuo and then the residue diluted with dichloromethane and a few drops of 25% aqueous NH4OH added until the mixture was measured at pH˜8. The mixture was then washed with water, the organic phase collected, concentrated in vacuo, and finally purified by chromatography (silica, 3 to 10% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxamide (15 mg, 39.1 μmol, 54%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.64 (s, 1H), 6.79 (d, J=4.3 Hz, 1H), 6.73 (s, 1H), 6.60 (s, 1H), 3.90 (s, 1H), 2.98 (m, 1H), 2.27 (s, 3H), 1.52-1.76 (m, 6H), 1.38 (m, 2H), 1.27 (d, J=7.0 Hz, 6H); MS (EI/CI) m/z: 384.1 [M+H].
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 36 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 36% of theory, C37H47N7O5 (669.8); EKA mass spectrum: (M+H)+=670; (M+H+Na)++=346.8; (M+2H)++=335.6.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)(=[O:3])[CH3:2].CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH3:16])[C:8]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2oc(=O)[nH]c2c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2oc(=O)n(C)c2c1
Yield: 74.2 %

Procedure:
5-Acetylbenzo[d]oxazol-2(3H)-one (0.5 g, 2.82 mmol), methyl iodide (0.6 g, 4.23 mmol), and cesium carbonate (1.37 g, 4.23 mmol) were dissolved in DMF (2 mL). The reaction mixture was irradiated by microwave for 30 minutes at 100° C. The solvent was removed and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 5-acetyl-3-methylbenzo[d]oxazol-2(3H)-one (0.4 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 1H), 7.80 (s, 1H), 7.00 (d, 1H), 3.48 (s, 3H), 2.60 (s, 3H); MS (ESI) m/z: Calculated for C10H9NO3: 191.1. found: 192.1 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[C:13]2[CH:14]=[CH:15]C(OC)=[N:17][C:18]=2[C:19](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:21]=1)=[O:11])[CH3:8].[CH3:32][N:33]([CH:35]=[O:36])[CH3:34]>O.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>[CH2:7]([O:9][C:10]([C:12]1[C:13]2[CH:14]=[CH:15][C:35](=[O:36])[N:33]3[CH2:34][C@H:18]([NH2:17])[C:19](=[CH:20][CH:21]=1)[C:32]=23)=[O:11])[CH3:8]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c2nc(OC)ccc12
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: [K+]
Solvent: O
Product: CCOC(=O)c1ccc2c3c1ccc(=O)n3C[C@@H]2N
Reaction time: 0.33 h

Procedure:
A solution of vinylboronic anhydride pyridine complex (1:1; 3.81 g) in DMF (240 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (731 mg) and stirred under nitrogen for 20 min. The reaction mixture was sequentially treated with K2CO3 (4.372 g) water (73 mL) and 2-methoxy-8-[[(trifluoromethyl)sulfonyl]oxy]-5-quinoline carboxylic acid ethyl ester (12.0 g; prepared in analogy to the corresponding n-butyl ester described in WO 2006/046552) and further stirred at 85° C. overnight. The reaction mixture was diluted with water and extracted with ether. The org. layer was dried over MgSO4, concentrated to dryness and purified by CC (Hex/EA, 4:1), affording a yellow oil (5.40 g; 66% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](OCC)=O)[CH:19]=[CH:20][CH:21]=1.C(O)C.[H-].[Na+]>O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][C:23]1[NH:14][C:12](=[O:13])[C:3]2[CH:4]=[N:5][N:6]([CH:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[C:2]=2[N:1]=1
Reactant: NC(=O)c1cnn(C2CCCC2)c1N
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1cnn2C1CCCC1

Procedure:
Under argon, 180 mg (0.91 mmol) of 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxamide and 575 mg (2.72 mmol; 3 equiv.) of ethyl (3-chlorophenyl)acetate are introduced into 3.5 ml of absolute ethanol. At 0° C., 127 mg of sodium hydride (60% dispersion in mineral oil; 3.18 mmol; 3.5 equiv.) are slowly added in a countercurrent of argon. The resulting mixture is slowly warmed and stirred under reflux for 18 h. The mixture is worked up by adding 50 ml of water and extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:4][O:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Yield: 88.9 %

Procedure:
18.8 ml (151 mmol) (2,2-dimethyl-[1,3]dioxolan-4-yl) -methanol and 28.6 g (150 mmol) toluene-4-sulfonyl chloride were stirred for 16 h at room temperature in 7 ml pyridine, it was poured onto 400 ml water, extracted twice with ethyl acetate, the combined ethyl acetate phases were washed with water, the organic phase was dried with sodium sulfate, filtered, the solvent was removed in a vacuum and 38.2 g (88%) toluene-4-sulfonic acid-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-ester was obtained as a colourless oil. MS (m/e)=286.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCCC4)CC3)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 54.9 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (17 mg, 0.034 mmol) in DCM (2 mL) was added 4-(1-pyrrolidinyl)piperidine (15 mg, 0.10 mmol). The resultant solution was stirred at room temperature over might. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (11 mg, 55%). LC-MS m/z 592 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.34 (m, 2H), 1.68 (m, 3H), 1.90 (m, 5H), 2.31 (s, 3H), 2.36 (m, 1H), 2.68 (m, 6 H), 3.37 (m, 2H), 4.11 (m, 2H), 4.42 (m, 2H), 7.16 (m, 2H), 7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH:13]1[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]1)[C:6](=[O:12])[NH:7]2.C(Cl)(=O)OC(Cl)C>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:6](=[O:12])[NH:7]2
Reactant: O=C1Nc2cccc(Cl)c2CN1C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C1Nc2cccc(Cl)c2CN1C1CCNCC1
Temperature: 0 °C

Procedure:
An ice-cold solution of 6.3 g (0.0177 mol) of 5-chloro-3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-quinazolinone (prepared analogously to Example A4e)) in 50 ml of dichloromethane was mixed dropwise with 3.34 g (0.0234 mol) of (α-chloroethyl chlorocarbonate whilst maintaining a reaction temperature of 0° C., after which the mixture was allowed to come back slowly to room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 50 ml of methanol and refluxed for 4 hours. After cooling, the colourless precipitate formed was suction filtered. Yield: 2.0 g (42.5% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of ethyl 4-[4-(tert-butyloxycarbonyl)-1-piperazinyl]benzoate (240 mg, 0.718 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL), and the resulting mixture was stirred for 3 hr. The mixture was concentrated in vacuo and the residue was made basic by the addition of sat. NaHCO3, followed by extraction with CHCl3 (2×100 mL). The combined extracts were dried over Na2CO3 and evaporated to give 168 mg ethyl 4-(1-piperazinyl)benzoate (100%) as a yellow oil. 1H-NMR (CDCl3) δ 1.37 (3 H, t, J=7.3 Hz), 3.03 (4 H, t, J=4.9 Hz), 3.29 (4 H, t, J=4.9 Hz), 4.33 (2 H, q, J=7.3 Hz), 6.87 (2 H, dt, J=8.8, 2.4 Hz), 7.91–7.94 (2 H, m).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[NH:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)=[O:15])=[C:9]([C:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=2)[CH:8]=1)[OH:6])C.[OH-].[K+].C(O)(C(F)(F)F)=O>CCO>[C:21]([C:18]1[NH:17][C:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH:5]([OH:6])[C:4]([OH:31])=[O:3])=[CH:8][C:9]=2[C:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=2)=[O:15])=[N:20][CH:19]=1)#[N:22]
Reactant: CCOC(=O)C(O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC1(C)CC=C(c2cc(C(O)C(=O)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of [4-[(5-cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-hydroxy-acetic acid ethyl ester (as prepared in the previous step)(30.0 mg, 71 μmol) in 0.2 mL of EtOH at RT was added a 2N KOH solution (71 uL, 14.2 μmol) and the reaction stirred for 2 h. The pH was then adjusted to 2 with a 2 M TFA solution and the title compound was purified by RP-HPLC, eluting with a linear gradient of 20% to 50% CH3CN in 0.1% TFA/H2O over 10 min to give 20 mg (71%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.24 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.40 (dd, J=8.4, 2.1 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 5.78 (m, 1H), 5.15 (s, 1H), 2.33 (m, 2H), 2.10 (m, 2H), 1.62 (t, J=6.3, 6.3 Hz, 2H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O2, 395.2 (M+H). found 395.1.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:26]3[C:17](=[CH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.O>[CH:16]1[C:17]2[C:26](=[CH:25][C:24]3[C:19]([CH:18]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:27]=[CH:28][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:29])[C:3]([OH:30])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3cc4ccccc4cc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3cc4ccccc4cc3c2)cc1
Yield: 75.8 %

Procedure:
A mixture of 4-[[2-(2-anthracenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.615 g) in hot tetrahydrofuran (100 mL) was treated with 1N sodium hydroxide (4 mL) and diluted with water. The resulting solids were recovered by filtration and stirred in a mixture of dichloromethane and excess 2N hydrochloric acid until the solids dissolved. The organic layer was separated, dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane gave 0.45 g of 4-[[2-(2-anthracenyloxy) ethyl]oxy]-alpha-oxobenzene-acetic acid as a colorless solid, mp 213°-214° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Br.Br[CH:7]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]1=O.[OH-].[Na+]>>[O:3]1[C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:1]=[C:2]1[NH2:4]
Reactant: O=C1CCNCCC1Br
Reactant: NC(N)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2c(o1)CCNCC2
Temperature: 70 °C
Reaction time: 24 h
Yield: 23.8 %

Procedure:
6.6 g urea was added to 6 g 5-bromo-azepan-4-one hydrobromide. The mixture was stirred 24 h at 70° C. The reaction was basified with 4 N NaOH and extracted with chloroform and ethylacetate. The combined organic layers were evaporated to yield 800 mg of the desired product.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH:34]2[CH2:37][CH2:36][NH:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[C:28]1([CH:34]2[CH2:37][CH2:36][N:35]2[C:23]([C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[O:24])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: c1ccc(C2CCN2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CCC1c1ccccc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Combine 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (125 mg, 0.33 mmol) and 2-phenyl-azetidine (100 mg, 0.75 mmol, excess) in dichloromethane (1.0 mL) and triethylamine (0.300 mL, 2.15 mmol, excess) and add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate (BOP Reagent) (0.150 mg, 0.33 mmol) at room temperature. Stir for 30 minutes, load entire reaction directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 149 mg of (2-Phenyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a glassy solid (92%). LRMS: MH+ 493.08.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][P:26](=[O:43])([O:35]CC3C=CC=CC=3)[O:27]CC3C=CC=CC=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][P:26](=[O:27])([OH:35])[OH:43])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Solvent: O
Solvent: CO
Product: O=P(O)(O)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Temperature: 0 °C
Yield: 48 %

Procedure:
A solution of 1.20 g, (1.73 mmol) phosphoric acid dibenzyl ester (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester in 40 ml MeOH and 6 ml water was hydrogenated at room temperature (20 bar, 5 h). The reaction mixture was concentrated to 20 ml and 500 ml water were added. The reaction mixture was filtered and the catalyst was washed with water. The filtrate was concentrated under reduced pressure until the product precipitates. The mixture was then cooled to 0° C. and 200 ml MeOH were added dropwise. After two hours the solid was filtered, washed with cold MeOH and dried at 60° C. under high vacuum to give 380 mg (0.83 mmol, 48%) of phosphoric acid mono-{(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl} ester as colorless crystalls.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH2:8][O:9][C:10](/[CH:12]=[CH:13]/[CH2:14]P(OCC)(OCC)=O)=[O:11].[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=O.Cl>O1CCCC1.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]([CH3:23])=[CH:14][CH:13]=[CH:12][C:10]([O:9][CH2:8][CH3:7])=[O:11])=[CH:27][CH:28]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=CC=C(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A stirred solution of 25.3 grams (0.230 mole) of potassium tert.-butoxide in 250 mL of tetrahydrofuran was cooled to 0° C., and a solution of 56.5 grams (0.230 mole) triethyl 4-phosphonocrotonate in 50 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature at about 0°-10° C. The complete addition required about 30 minutes. The reaction mixture was then stirred for one hour at 0°-5° C., and then 26.6 grams (0.180 mole) of 4-methoxyacetophenone was added in one portion. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was made acidic with an aqueous 2N hydrochloric acid solution and diluted with about 200 mL of water. The mixture was extracted with two 250 mL portions of diethyl ether. The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was taken up in 150 grams of silica gel, and the solvent was removed under reduced pressure. The silica gel mixture was placed on top of a column of silica gel, and the mixture was eluted with 10% ethyl acetate in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.9 grams of ethyl 5-(4-methoxyphenyl)-2,4-hexadienoate. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5](O)=[O:6].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.[N:55]1([C@H:60]2[CH2:65][CH2:64][CH2:63][CH2:62][C@H:61]2[NH2:66])[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C)C=O>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:3]([C:2]([F:1])([F:18])[F:19])[C:4]=1[C:5]([NH:66][C@@H:61]1[CH2:62][CH2:63][CH2:64][CH2:65][C@@H:60]1[N:55]1[CH2:56][CH2:57][CH2:58][CH2:59]1)=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
2,4-Bis(trifluoromethyl)-6-methoxy-benzoic acid (200 mg, 0.69 mmol) was dissolved in 5 mL dimethylformamide. N,N-Diisopropyl ethyl amine (359 mg, 2.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (264 mg, 0.69 mmol) were added. After 5 minutes of stirring at room temperature cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) (171 mg, 0.71 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-2-methoxy-N-(2-pyrrolidin-1-yl-cyclohexyl)-4,6-bis-trifluoromethyl-benzamide as a white solid (158 mg, 52%), MS: m/e=439.2 [(M+H)+].