Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:12]([O:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=2)(=[O:24])=[O:23])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41](N(CCCC)CCCC)[CH2:42]CC.C(O)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH2:41]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([S:22]([O:21][C:12]2[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:23])=[O:24])=[CH:26][C:27]=1[OH:34])[CH3:42]
Reactant: O=C(c1ccccc1)c1cc(-c2ccccc2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1
Reactant: CCCCN(CCCC)CCCC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(S(=O)(=O)Oc2c(-c3ccccc3)cc(C(=O)c3ccccc3)cc2-c2ccccc2)cc1O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A stirred solution containing 4-(5'-benzoyl-[1,1';3',1"]terphenyl-2'-yloxysulfonyl)-2-hydroxy-benzoic acid (0.106 g, 0.192 mmol), tributylamine (0.110 mL, 0.462 mmol), ethanol (0.0677 mL, 1.15 mmol) and 2-chloro-1-methyl pyridinium iodide (0.0607 g, 0.231 mmol) in CH2Cl2 (2 mL) was refluxed for 18 h. The reaction was cooled to ambient temperature, quenched with 1N HCl (20 mL) and extracted with EtOAc. The organic extracts were successively washed with 1N HCl (3×), with brine (3×), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 0.039g (35%) of the title compound as a white solid, mp 75-85° C. 1H NMR (DMSO-d6) δ 1.36 (t, 3H), 4.38 (q, 2H), 6.67 (d, 1H), 6.73 (dd, 1H), 7.30-7.36 (m, 6H), 7.45-7.52 (m, 5H), 7.57-7.61 (m, 2H), 7.68-7.71 (m, 3H), 7.84 (d, 2H), 10.60 (s, 1H). mass spectrum (El) m/z 578 (M+). Anal. Calcd. for C34H26O7S 0.5H2O: C,69.49; H,4.63; N,0.00. Found: C,69.38; H,4.76; N,0.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O)(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1.[NH:52]([CH2:55][CH3:56])[CH2:53][CH3:54].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][N:52]([CH2:55][CH3:56])[CH2:53][CH3:54])(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:50][CH:51]=1
Reactant: CCNCC
Reactant: COC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3C=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)Cc1ccccc1CS(=O)(=O)NCCc1c(CCCc2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 41.3 %

Procedure:
As outlined in Example 17, Step 1 methyl 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate (Example 16, Step 5, 58 mg, 0.081 mmol) was reacted with HNEt2 (0.022 mL, 0.21 mmol) and NaBH(OAc)3 (56 mg, 0.26 mmol) in DCE (2 mL) to afford methyl 4-{3-[5-chloro-2-{2-[({2-[(diethylamino)methyl]benzyl}sulfonyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoate (26 mg, 41%) and the side product methyl 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(hydroxymethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoate (8.6 mg, 15%), both as white solids.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH3:16])=[O:14].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:13](=[O:14])[O:15][CH3:16])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 15 ml of pyridine was dissolved 3.00 g of 6-(trifluoromethyl)pyridin-3-amine, and then 2.1 ml of methyl chloroformate was added thereto under ice-cooling, followed by 2 hours of stirring at room temperature. Under ice-cooling, 30 ml of a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by 1 hour of stirring. Thereafter, the precipitated crystals were filtrated and, after washing with water, dried under reduced pressure to obtain 3.88 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[OH:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>C1COCC1>[C:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
To a mixture of 2,3,4-trifluorophenol (5.2 g) and acetic anhydride (3.98 mL) in THF (50 mL) was added triethylamine (5.87 mL) at room temperature, and the mixture was stirred for 1 hr and concentrated under reduced pressure. Water and ethyl acetate were added to the residue, the organic layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.70 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([N:36]([CH3:37])[C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CNC1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(SCCN3CCC(N(C)C(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (26 mg, 0.11 mmol, 1.0 eq) is added at room temperature to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine (40 mg, 0.11 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (45 mg, 0.11 mmol, 1.0 eq), and triethylamine (16 μL, 0.11 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amide as a yellow solid (22 mg, 35% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: C=CCC(C)(C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC(C)(C)C(=O)OCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 2,2-dimethyl-4-pentenoic acid (11.5 g, 90 mmol) in DMF (250 mL) at room temperature, was added potassium tert-butoxide (11.1 g, 99 mmol). The reaction mixture was stirred at 60° C. for 1 h. 4-Methoxybenzylchloride (16.9 g, 108 mmol) was added and the reaction mixture was stirred at 60° C. for 4 h. The DMF was evaporated under vacuum, the residue was dissolved in ether (500 mL) and washed with water (3×200 mL). The organic phase was dried with Na2SO4 and evaporated to give 21.4 g of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[F:14])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[S:26]>CO.C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([NH:11][C:25]([NH:24][C:18]2[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])=[S:26])[C:8]([NH:12][CH3:13])=[CH:7][C:6]=1[F:14])[CH3:2]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cc(N)c(NC)cc1F
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(NC)cc1F

Procedure:
Prepared analogously to example 131d from 5-amino-2-fluoro-4-methylamino-benzoic acid ethyl ester and 1,3-dichloro-2-isothiocyanato-benzene in methanol and acetonitrile.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1C=CC=CC=1>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:4][C:3](=[O:5])[C@@H:2]2[CH2:6][CH2:7][CH2:8][NH:1]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1
Yield: 118.3 %

Procedure:
Preparation 6 ##STR64## (a) A mixture solution of 5.0 g of L-proline, 9.91 g of p-toluenesulfonic acid monohydrate and 6.65 g of p-nitrobenzyl alcohol in 100 ml of benzene was refluxed for 2 days by using Dean-Stark trap. After reaction, the solvent was removed under reduced pressure and the resulting residue was washed with diethyl ether to give 21.7 g of L-proline p-nitrobenzyl ester p-toluenesulfonic acid salt as oil. Then, a mixture solution of 12.17 g of Boc-glycine and 13.32 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride in 150 ml of ethylene chloride was stirred for 25 minutes under ice-cooling at nitrogen atmosphere. To this reaction mixture was added a solution of 29.36 g of the compound obtained above in 100 ml ethylene chloride and the reaction mixture was stirred overnight at room temperature. After reaction, the reaction mixture was washed with 10% citric acid aqueous solution, 4% sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give 8.00 g of [N-(t-butoxycarbonyl)glycyl]L-proline p-nitrobenzyl ester [Compound (22)].
Reaction SMILES: O.NN.P(Cl)(Cl)(Cl)(Cl)Cl.Br.F[C:12]1C=CC(OC)=CC=1C#N.[F:22][C:23]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>CO>[F:22][C:23]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:24]=1[C:25]([O:27][CH3:12])=[O:26]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: COc1ccc(F)c(C#N)c1
Agent: Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(O)ccc1F

Procedure:
In the presence of hydrazine hydrate/glacial acetic acid, phthalic anhydride (3a) with substituent R was transformed into R-substituted phthalhydrazide (3b), which subsequently generated substituted dichlorophthalazine compounds (3c) under the action of phosphorus pentachloride. In another aspect, under the action of hydrobromic acid, 2-fluoro-5-methoxybenzonitrile (3d) was converted to 2-fluoro-5-hydroxybenzoic acid (3e), which was esterificated with methanol to give methyl 2-fluoro-5-hydroxybenzoate (3f). Under the action of sodium hydride, the prepared dichlorophthalazine compounds with substituent R (3c) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate with substituent R (3g), 3g was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxy)benzoate (3h) in the presence of AcOH/NaOAc under the reflux condition, 3h was then hydrolyzed under alkali condition into substituent-contained 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (3i), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R and R′ is as described above.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:17])[N:10]([C@@H:18]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]3[O:20]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[N:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[F:41][C:42]1[N:47]=[CH:46][C:45]([C:2]2[S:6][C:5]([CH2:7][C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]=4[CH3:17])[N:10]([C@@H:18]4[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]4[OH:20])[CH:9]=3)=[CH:4][CH:3]=2)=[CH:44][CH:43]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1cccc2c1c(Cc1ccc(-c3ccc(F)nc3)s1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
3-(5-Bromothiophen-2-yl-methyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 45-(3) and 6-fluoropyridine-3-boronic acid were treated in a manner similar to Example 45-(4) and 2-(7) to give the titled compound as a colorless powder. APCI-Mass m/Z 485 (M+H). 1H-NMR (DMSO-d6) δ 2.50 (s, 3H), 3.20-3.50 (m, 4H), 3.70 (m, 2H), 4.40 (s, 2H), 4.54 (t, J=5.4 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.7 Hz, 1H), 5.17 (d, J=5.7 Hz, 1H), 5.36 (d, J=9.0 Hz, 1H), 6.75 (d, J=7.1 Hz, 1H), 6.87 (d, J=3.4 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 7.19 (dd, J=8.6, 2.7 Hz, 1H), 7.33 (s, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H), 8.16 (dt, J=8.2, 2.4 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH:16]=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1CCC=O
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
To a solution of N-tert-butoxycarbonyl-3-piperidin-2-yl-propan-1-ol (0.372 g, 1.53 mmol) in CH2Cl2 (7.5 mL), at room temperature, was added sequentially 3 Å molecular sieves (0.814 g), N-methylmorpholine N-oxide (0.278 g, 2.37 mmol) and tetrapropylammonium perruthenate (56 mg, 0.16 mmol). After 90 minutes, the mixture was filtered through a short column of silica gel and the cake was washed with ethyl acetate. The solvent was removed from the filtrate under reduced pressure to provide 0.32 g (86%) of N-tert-butoxycarbonyl-3-piperidin-2-yl-propionaldehyde as a green oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Oc3ccc(Cl)cc3)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ccc(Oc2ccc(NC3CCNCC3)cc2)cc1
Reaction time: 17 h
Yield: 203.7 %

Procedure:
In a similar manner as described above in Paragraph A, a solution of 1,1-dimethylethyl 4-[[4-(4-chlorophenoxy)phenyl]amino]-1-piperidinecarboxylate (1.34 g, 3.3 mmol) in dichloromethane (10 mL) was stirred as a solution of 4 M hydrochloric acid in dioxane (3.3 mL, 13.3 mmol) was added. The reaction was stirred for 17 hours. Solvent was removed to yield 1.14 g of N-[4-(4-chlorophenoxy)phenyl]-4-piperidinamine hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[S:33]1[CH:37]=[N:36][N:35]=[C:34]1[NH2:38].C(N(C(C)C)CC)(C)C>CC#N>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10]([NH:38][C:34]2[S:33][CH:37]=[N:36][N:35]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc(Cl)nc1
Yield: 79.3 %

Procedure:
A solution of 3-(6-chloro-pyridin-3-yl)-2,2-dimethyl-3-phenyl-propionic acid (Preparation 4, 100 mg, 0.345 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (132 mg, 0.69 mmol) and 1-hydroxy-7-benzotriazole (HOBt) (93 mg, 0.69 mmol), 1,3,4-thiadiazol-2-amine (103 mg, 1.04 mmol) and diisopropylethyl amine (0.21 ml, 1.21 mmol) in CH3CN (1 mL) was heated at 75° C. for 12 hours. The reaction mixture was filtered, concentrated and purified by silica gel flash chromatography using 50% ethyl acetate in hexanes to give 3-(6-chloro-pyridin-3-yl)-2,2-dimethyl-3-phenyl-N-[1,3,4]thiadiazol-2-yl-propionamide as a white solid. (102 mg, 79.3% yield).). 1H NMR (400 MHz, CDCl3): δ 1.31 (s, 3H), 1.32 (s, 3H), 4.57 (s, 1H), 7.15 (m, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.85 (m, 1H), 8.26 (br s, 1H), 8.90 (s, 1H). LC/MS (m/z) 373.19 [(M+H)+]; HPLC Rt: 2.913 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C1COCC1>[Br:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:3]=1)=[O:38]
Reactant: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(N)c2)nc1=O
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(NC(=O)c3cccc(Br)c3)c2)nc1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a mixture of 2-(3-amino-phenylamino)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (§) (20.0 mg, 0.06 mmol) in THF (2 mL), triethylamine (13 μL, 0.09 mmol) and 3-bromobenzoylchloride (10 μL, 0.07 mmol) was added and stirred at 50° C. for 2 hrs. The mixture was quenched with concentrated HCl and purified on BondElut® SCX (Varian Incorporated). Formed solid was washed with CH2Cl2 to give the title compound (25.3 mg, 81%). 1H-NMR (400 MHz, d6-DMSO) δ 10.43 (s, 1H), 9.68 (s, 1H), 8.15 (t, 1H), 8.08 (s, 1H), 7.97 (dt, 1H), 7.81 (ddd, 1H), 7.75 (brd, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.36 (dt, 1H), 7.31 (t, 1H), 7.05-6.98 (2H), 6.42 (s, 1H), 3.99 (t, 2H), 3.84 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 517, 519.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:27][CH:28]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(N)nc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (46 mg, 61%), MS (ISN) m/z=304.5 [(M+H)+], mp 305° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1CCCC1>Cl[Pd]Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Ic1ccccc1
Reactant: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd]Cl
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCC#Cc2ccccc2)cc1
Yield: 17.7 %

Procedure:
General procedure A was followed using the product from step 3, Example 1 (165 mg, 0.498 mmol), iodobenzene (85 mg, 0.416 mmol), PdCl2 (2.5 mg, 0.014 mmol), pyrrolidine (0.2 mL, 2.37 mmol), water (0.53 mL) to give the title compound (30 mg, 15%).
Reaction SMILES: [NH2:1][O:2][CH2:3]CCC(O)=O.[C:9]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10]1.C1(=O)OC(C)CC1>>[NH2:1][O:2][CH2:3][CH2:12][CH2:11][CH2:10][C:9]([OH:13])=[O:14]
Reactant: NOCCCC(=O)O
Reactant: O=C1CCCO1
Solvent: CC1CCC(=O)O1
Product: NOCCCCC(=O)O

Procedure:
5-Aminooxyvaleric acid is prepared in the same manner using the procedure of Preparation 6 for 4-aminooxybutyric acid except that the γ-butyrolactone is replaced by γ-valerolactone.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1>N1CCCCC1.C(O)C>[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(Br)ccc21
Yield: 92.3 %

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 106 mg 6-bromo-2-oxindole, and 3 drops piperidine in 3 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 172 mg (92%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([C:7](=[O:28])[CH2:8][CH2:9][NH:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12]([O:14]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]#[C:30][OH:31]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:11]1[N:10]([CH2:9][CH2:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:28])[C:30](=[O:31])[NH:29][C:12]1=[O:14])=[O:24])[CH3:27]
Reactant: N#CO
Reactant: CCOC(=O)CCCCCCC(NCCC(=O)C1CCCCC1)C(=O)OCC
Product: CCOC(=O)CCCCCCC1C(=O)NC(=O)N1CCC(=O)C1CCCCC1

Procedure:
Reaction of diethyl 2-((3-cyclohexyl-3-oxopropyl)amino)nonanedioate (20.8 g) with cyanic acid using the general procedure of Example 2d afforded 5-(6-ethoxycarbonylhexyl)-1-(3-cyclohexyl-3-oxopropyl)hydantoin which was converted to the corresponding acid which crystallised from ether, m.p. 77.5°-78.5° C.