Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH2:12][O:13][CH2:14][B-](F)(F)F)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Na+].O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.O>[CH2:14]1[C:2]2[CH:11]=[C:10]3[C:5](=[CH:4][C:3]=2[CH2:12][O:13]1)[CH:6]=[CH:7][CH:8]=[CH:9]3
Reactant: F[B-](F)(F)COCc1cc2ccccc2cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc2cc3c(cc2c1)COC3
Temperature: 100 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
To the mixture of sodium (((3-bromo-2-naphthyl)methoxy)methyl)trifluoroborate (30 mg, 0.088 mmol) synthesized in Example 6 and 1,4-dioxane (1.0 ml), water (0.15 ml), cesium carbonate (86 mg, 0.26 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (7.2 mg, 0.018 mmol), palladium(II) acetate (2.0 mg, 0.009 mmol) were added at room temperature, and the obtained reaction mixture was then stirred at 100° C. (an outer temperature) for 16 hours. The reaction mixture was cooled to room temperature, and then water and dichloromethane were added thereto, followed by filtration with Celite. The organic layer of the filtrate was separated and washed with saturated saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1), thereby obtaining the entitled compound (10 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.[CH:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)=[CH:26][CH:25]=1)([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH:20]([CH3:21])[CH3:22])=[CH:25][CH:26]=3)[O:31][C:32]=2[CH3:38])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCO
Reactant: CCOC(Cc1ccc(O)c2ccsc12)C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)c2ccsc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-benzo[b]thiophen-7-yl)-propionic acid methyl ester was reacted with 2-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [PCT Int. Appl. (2000), WO0008002A1] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropoxy-phenyl-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-7-yl)-propionic acid as light yellow amorphous solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]2)=[CH:16][C:15]=1[O:30][CH3:31].IC>C1COCC1.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23]([CH3:1])([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]2)=[CH:16][C:15]=1[O:30][CH3:31]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COC(=O)C1(C)CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A 50-mL 2-neck round bottom flask was fitted with a nitrogen inlet and rubber septum and charged with N,N-diisopropylamine (0.598 mL, 4.26 mmol) in anhydrous THF (15 mL). The solution was cooled to −70° C., treated with n-butyllithium (3.05 mL, 4.26 mmol) and stirred for 30 min. A solution of methyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (1.10 g, 3.88 mmol) in THF (3 mL) was added dropwise to the reaction and the resulting mixture was stirred at −70° C. for 1 h. After this time, the mixture was treated with iodomethane (0.253 mL, 4.07 mmol) and slowly warmed to RT. TLC and LC-MS (m/z=298.21) indicated the reaction was complete. The mixture was treated with water (25 mL) and extracted with EtOAc (3×30 mL). The extract was dried (Na2SO4) and concentrated on a rotary evaporator to give methyl 1-(4-chloro-3-methoxyphenyl)-4-methylpiperidine-4-carboxylate (1.06 g, 3.56 mmol, 92% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.17 (1 H, d, J=8.56 Hz), 6.48 (1 H, s), 6.44 (1 H, dd, J=8.69, 2.14 Hz), 3.86 (3 H, s), 3.70 (3 H, s), 3.38 (2 H, ddd, J=12.72, 4.03, 3.90 Hz), 2.82-2.91 (2 H, m), 2.19-2.26 (2 H, m), 1.52-1.64 (2 H, m), 1.24 (3 H, s).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:12][C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:13])[N:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1c(Cl)ccnc1Cl
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(Cl)ccnc1C
Temperature: 70 °C
Yield: 30.3 %

Procedure:
A mixture of methyl 2,4-dichloronicotinate (2 g, 9.71 mmol), trimethylboroxine (1.462 g, 11.65 mmol), Cs2CO3 (6.33 g, 19.42 mmol) and PdCl2(dppf) (0.710 g, 0.971 mmol) in 1,4-dioxane (30 mL) and water (2 mL) was purged with nitrogen for 5 min and heated at 70° C. for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc-hexane mixture) to afford methyl 4-chloro-2-methylnicotinate (550 mg, 2.94 mmol, 31% yield) as a red oil. 1H NMR (300 MHz, CD3OD) δ ppm 8.44 (d, J=5.7 Hz, 1H), 7.43 (d, J=5.7 Hz, 1H), 3.98 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([CH:16]=O)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:18]1[C:27]2[CH:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]3[C:41](=[O:42])[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]3=[O:43])[CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([CH2:16][N:28]([CH:26]2[C:27]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][CH2:24][CH2:25]2)[CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[C:34](=[O:43])[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]2=[O:42])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1CN(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21

Procedure:
Using General Procedure B, reaction of 3-(tert-Butyldimethylsilanyloxymethyl)-pyridine-2-carbaldehyde, 2-[4-(5,6,7,8-Tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dione and NaBH(OAc)3 in CH2Cl2 gave 2-{4-[[3-(tert-Butyldimethylsilanyloxymethyl)-pyridin-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a light brown solid. 1H NMR (CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H), 1.31 (m, 2H), 1.49 (quintet, 2H, J=7.5 Hz), 1.59 (m, 1H), 1.85-2.08 (m, 3H), 2.47 (m, 1H), 2.59 (m, 2H), 2.67 (m, 1H), 3.49 (t, 2H, J=7.5 Hz), 3.90 (m, 1H), 3.96 (d, 1H, J=12.0 Hz), 4.11 (d, 1H, J=12.0 Hz), 4.98 (d, 1H, J=15.0 Hz), 5.20 (d, 1H, J=15.0 Hz), 6.99 (m, 1H), 7.13 (m, 1H), 7.28 (d, 1H, J=7.5 Hz), 7.68 (m, 2H), 7.80 (m, 2H), 7.82 (d, 1H, J=7.5 Hz), 8.32 (d, 1H, J=3.0 Hz), 8.42 (d, 1H, J=3.0 Hz).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20]>CO.C(O)C>[CH3:18][S:19]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: CS(N)(=O)=O
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)NC(=N)CCSCc1csc(NC(=N)N)n1
Yield: 56.9 %

Procedure:
In 10 ml of methanol were dissolved 1 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 0.38 g of methanesulfonamide and after causing reaction for 48 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue formed was dissolved in 3 ml of ethanol and the solution was allowed to cool, thereby white crystals deposited. The crystals were collected by filtration and dried to provide 0.7 g of N-methanesulfonyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine. The product shows the following physicochemical properties:
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.S1C=CC=C1>[Pd].CO>[C:11]1([CH2:10][N:9]([CH2:8][C@@H:7]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[OH:1])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNCc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](O)C1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 1,1-dimethylethyl (trans)-3-hydroxy-4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate (intermediate (1-d) in WO-99/02156) (0.426 mol), benzaldehyde (0.5 mol) and palladium-on-carbon (10%) (5 g) in a thiophene solution (5 ml) and methanol (1000 ml) was stirred at 70-80° C. overnight. The solvent was evaporated. The residue was partitioned between DCM (150 ml) and 5% aqueous NaOH (150 ml). The mixture was separated into its layers. The aqueous layer was extracted with DCM. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE and a drop of ACN. The precipitate was filtered off and dried, yielding 2.35 g 1,1-dimethylethyl (trans)-4-[[bis(phenylmethyl)amino]methyl]-3-hydroxy-1-piperidinecarboxylate (intermediate 27), mp. 133° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:39])[CH3:38])[C:28]([CH:40]=[O:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CO>O1CCCC1>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:35])([CH3:36])[CH2:32][C:31]2[N:30]=[C:29]([CH:37]([CH3:38])[CH3:39])[C:28]([C@H:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[OH:41])=[C:27]([I:42])[C:26]1=2)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -20 °C
Reaction time: 5 h

Procedure:
1.1 ml 4-iodobenzotrifluoride are dissolved in 60 ml tetrahydrofurane and cooled to −20° C. 3.7 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane are added dropwise and the solution is stirred for further 5 hours. Then the solution is cooled to −40° C. and 1.17 g (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 5 ml tetrahydrofurane are added dropwise. The mixture is stirred for 12 hours while warming to room temperature. Then it is cooled to 0° C., 10 ml methanol are added and it is stirred for 30 minutes. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 95:5 to 80:20).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:37]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([S:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:40])=[O:39])[CH:37]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
5-Fluoro-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)-phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 5-fluoro-2-methylbenzenesulfonylchloride (50 mg, 0.239 mmol) according to general method 3 to give 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 505.2; Calcd 505.13; 1H-NMR δ 7.73-7.17 (m, 8H), 6.83 (d, 1H), 6.68 (dd, 1H), 6.50 (dd, 1H), 3.27-3.17 (m, 8H), 2.55 (s, 3H).
Reaction SMILES: C[O-].[Na+].C(O)C.[NH2:7][C:8]([NH2:10])=[S:9].[C:11]([CH2:15][C:16](OC)=[O:17])(=O)[CH2:12][CH3:13]>O>[SH:9][C:8]1[NH:10][C:16](=[O:17])[CH:15]=[C:11]([CH2:12][CH3:13])[N:7]=1
Reactant: NC(N)=S
Reactant: CCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cc(=O)[nH]c(S)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.8 %

Procedure:
To a solution of sodium methoxide(24 g, 0.44 mol) and ethanol(180 ml) were added thiourea(15.22 g, 0.2 mol) and methyl propionylacetate(25.1 ml, 0.2 mol). After distillating solvent slowly, water(200 ml) was added to the reaction mixture, which was then heated to reflux for 30 minutes. Active carbon was added to the reaction mixture, which was then stirred for 5 minutes and filtered. The filtrate was cooled to a room temperature and acidified by glacial acetic acid and the resulting solid was filtered and dried to give 29 g of the titled compound. (Yield: 93%)
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.C(N)CN>>[O:39]=[S:30]1(=[O:38])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][CH2:14][CH2:9][NH2:8])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Solvent: NCCN
Product: NCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccccc12

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 383, 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (m, 1 H), 7.81 (d, J=7.83 Hz, 2 H), 7.55 (m, 1 H), 7.47 (m, 1 H), 7.33 (m, 2 H), 7.04 (m, 1 H), 5.94 (m, 1 H), 5.12 (s, 2 H), 3.57 (t, J=4.55 Hz, 2 H), 3.43 (t, J=6.32 Hz, 2 H), 3.33 (m, 2 H), 2.97 (t, J=6.44 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[CH:12]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[C:16]=1[S:27]([NH:30][NH2:31])(=[O:29])=[O:28])([CH3:14])[CH3:13]>CO>[CH:24]([C:17]1[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=[C:15]([CH:12]([CH3:13])[CH3:14])[C:16]=1[S:27]([NH:30][N:31]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:9])(=[O:28])=[O:29])([CH3:25])[CH3:26]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Agent: Cl
Solvent: CO
Product: CC(=NNS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1ccc(C)cc1
Yield: 86.4 %

Procedure:
1-(4-Methylphenyl)ethanone (2.28 g) and concentrated hydrochloric acid (1 ml) were added to a stirred solution of 2,4,6-triisopropyl benzenesulphonylhydrazine (5 g) in methanol (20 ml). The resulting mixture was stirred until a dense white precipitate formed. The precipitate was removed by filtration and washed with cold methanol to yield 1-(4-methylphenyl)ethanone 2,4,6-triisopropylbenzenesulphonylhydrazone (6 g) as a fine white crystalline solid.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10].S(=O)(=O)(O)O.O.C(#[N:20])C>>[NH2:20][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: O[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CC#N
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Cis-1,2-indandiol (1.0 g) was dissolved in acetonitrile (20 mL), cooled to -40° C., and fuming sulfuric acid (21% SO3, 0.8 mL) was added. The mixture was aged for 1 hour with gradual warming to 0° C. Water was added and the mixture heated to 80° C. for 1 hour to provide an aqueous solution of cis-1-amino-2-indanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.CO[C:43]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:44]=1>O1CCCC1>[C:43]1([O:18][CH2:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:19]([CH3:21])[CH3:20])[N:12]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:44]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1=CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1nc(CCOC2=CCCCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of the compound 22 (690 mg, 2 mmol) and p-toluenesulfonic acid hydrate (400 mg, 2.1 mmol) in a mixture of tetrahydrofuran (10 mL) - toluene (100 ML) was concentrated under reduced pressure. The residue was dried on an oil bath at 55° C. for 40 minutes. The residue was dissolved in toluene (100 mL), and 1-methoxycyclooctene (1.84 g, 10 mmol) was added thereto. The reaction mixture was heated with reflux over 1 hours and concentrated to a small quantity. After cooling down at room temperature, triethylamine (0.4 mL) was added thereto. The reaction mixture was purified by chromatography on an alumina column (eluate: hexane - ethyl acetate (15:1)) to give the compound 47 (790 mg, 87%). Mp 73-74° C. PMR (CDCl3 -0.1% d5 -Py): δH1.24 (6 H, d, J 4.6 Hz, (CH3)2C), 3.13 (2 H, t, J 4.2 Hz, CH2 -Im), 3.08 (1 H, m, (CH3)2CH), 3.51 (3 H, 8, NCH3), 3.96 (2 H, t, J 4.2 Hz, OCH2), 4.51(1 H, t, J 5.6 Hz, =CH), 6.77 (2 H, d, J 2 Hz, arom-H), 7.09 (1 H, t-like, arom-H). IR(KBr)cm-1 : 3436, 3056, 1659, 1568, 1533, 1500, 1160, 1094. Elementary analysis (for C23H30N2Ocl2S) Calcd. : C, 60.91% H, 6.67% N, 6.18% S, 7.07% Cl, 15.63% Found: C, 60.74% H, 6.69% N, 5.94% S, 6.83% Cl, 15.43%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:31]3[C:26](=[O:25])[CH:27]=[CH:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(O)nc1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(B(O)O)cc2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(=O)n(-c2ccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)cc2)c1
Reaction time: 8 h

Procedure:
A mixture of {4-[(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)methyl]phenyl}boronic acid (800 mg; 2.39 mmol; prepared as described for the synthesis of intermediate X.7 without BOC deprotection step), ethyl 6-hydroxypyridine-3-carboxylate (420 mg; 2.51 mmol), copper(II) acetate (250 mg; 1.38 mmol) and pyridine (210 μl; 2.60 mmol) in DCM (10 ml) is stirred overnight. The mixture is filtered and extracted with water. The organic layer is dried with sodium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient DCM/methanol 98:2→94:4) to yield ethyl 1-{4-[(4-{[(tertbutoxy)carbonyl]amino}piperidin-1-yl)methyl]phenyl}-6-oxo-1,6-dihydropyridine-3-carboxylate
Reaction SMILES: C[O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[N:13][C:14]=3[C:19]([NH2:21])=[O:20])[CH2:5][CH2:4]1.CO[C@@H]1CC[C@H](N2C(=O)NC3C2=NC(C2C=CC=C(O[Si](C(C)C)(C(C)C)C(C)C)C=2)=NC=3C(OC)=O)CC1.N>CO.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[N:13][C:14]=3[C:19]([NH2:21])=[O:20])[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@@H](n2c(=O)[nH]c3c(C(N)=O)nc(-c4cccc(O)c4)nc32)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@@H](OC)CC1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@@H](O)CC1
Reaction time: 16 h

Procedure:
9-(cis-4-Methoxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide. Methyl 9-(cis-4-methoxycyclohexyl)-8-oxo-2-(3-(triisopropylsilyloxy)phenyl)-8,9-dihydro-7H-purine-6-carboxylate (0.210 g, 377 mmol) was dissolved in methanol (15 mL) reacted with ammonia gas according to General Procedure G. After 16 h, the solution was condensed under reduced pressure and the resultant crude product diluted with tetrahydrofuran (15 mL) and 1.0M tetrabutylammonium fluoride in tetrahydrofuran (0.92 mL) was added. After two h, the resultant precipitate was filtered and washed with tetrahydrofuran followed by hexanes. The product was purified using reverse-phase preparative HPLC (20 to 100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) to afford the title compound (0.093 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.47 (s, 1H), 8.32 (s, 1H), 8.03 (d, J=7.59, 1H), 7.92 (s, 2H), 7.28 (t, J=7.59, 1H), 6.86 (dd, J=7.99, 2.39, 1H), 4.30 (m, 1H), 3.49 (s, 1H), 3.34 (s, 3H), 2.71 (m, 2H), 2.06 (s, 1H), 2.03 (s, 1H), 1.53 (m, 4H); MS (ESI) m/z 384.4. [M+1]+; mp 345-347° C.