Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1.CN(C)CCN(C)CCN(C)C.CCOC(C)=O>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:26]=[O:27])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
To 118B (625 mg, 2.46 mmol) in THF (10 mL) and N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.77 mL) was added n-BuLi (1.6M in hexane, 1.77 mL) at −78° C. After stiiring for 45 min at −35° C., DMF (0.94 mL) was added at at −78° C. and the reaction was slowly warmed up to rt. The mixture was stirred at rt for 1 h, diluted with EtOAc. The organic extracts were washed with saturated NaHCO3, brine and dried. The crude product was purified by column chromatography to give 118C (615 mg, 89% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.21 (s, 6H) 1.01 (s, 9H) 1.21 (t, J=7.47 Hz, 3H) 2.59 (q, J=7.47 Hz, 2H) 6.99 (dd, J=7.91, 2.20 Hz, 1H) 7.21-7.27 (m, 1H) 10.30 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]([C:44](=[O:49])[C:45]([F:48])([F:47])[F:46])[CH:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:3][CH2:2]1.C(O)C.CCCCCC>C(O)C>[CH:1]1([N:4]([C:44](=[O:49])[C:45]([F:46])([F:48])[F:47])[C@@H:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:3][CH2:2]1.[CH:1]1([N:4]([C:44](=[O:49])[C:45]([F:46])([F:48])[F:47])[C@H:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:3][CH2:2]1
Reactant: COc1c(C)cnc(CN2N=C3CC(N(C(=O)C(F)(F)F)C4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: CCO
Solvent: CCCCCC
Product: COc1c(C)cnc(CN2N=C3C[C@@H](N(C(=O)C(F)(F)F)C4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Product: COc1c(C)cnc(CN2N=C3C[C@H](N(C(=O)C(F)(F)F)C4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Yield: 33 %
Yield: 43 %

Procedure:
Di-tert-butyl {8-[cyclopropyl(trifluoroacetyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate (1.0 g) was dissolved in ethanol (20 ml) and optically resolved by AD column 50×500 mm (15% ethanol/n-hexane 50.0 ml/min). This operation was repeated three times to obtain di-tert-butyl {8-(S)-[cyclopropyl(trifluoroacetyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate (RT=70 min) (1.3 g, 43%) and di-tert-butyl {8-(R)-[cyclopropyl(trifluoroacetyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate (RT=130 min) (1.0 g, 33%).
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[NH:11]1[C:20](=[O:21])[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13].O[CH:23]1[C:28]2=[CH:29][C:30]3[CH:31]=[CH:32][C:33]4[C:42]5[C:41]=3[C:40]([C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[C:37]=5[CH:36]=[CH:35][CH:34]=4)=[C:27]2[CH:26](N2C3C(=O)NC(N)=NC=3N=C2)[CH:25](O)[CH:24]1O>>[CH:43]1[C:39]2[C:40]3[C:41]4[C:42]5[C:33]([CH:32]=[CH:31][C:30]=4[C:29]([C:17]4[NH:18][C:19]6[C:20](=[O:21])[NH:11][C:12]([NH2:13])=[N:14][C:15]=6[N:16]=4)=[C:28]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]4=3)=[CH:34][CH:35]=[CH:36][C:37]=5[C:38]=2[CH:46]=[CH:45][CH:44]=1
Reactant: Nc1nc2ncn(C3c4c(cc5ccc6cccc7c8ccccc8c4c5c67)C(O)C(O)C3O)c2c(=O)[nH]1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: Nc1ncnc2nc[nH]c12
Product: Nc1nc2nc(-c3c4ccccc4c4c5ccccc5c5cccc6ccc3c4c65)[nH]c2c(=O)[nH]1

Procedure:
##STR5## wherein R is adenine or guanine. The following compounds are exemplary: 7-(11,12,13-trihydroxy-11,12,13,14tetrahydrodibenzo[a,l]pyren-14-yl)guanine, and
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]12[NH:25][CH:22]([CH2:23][CH2:24]1)CC2.CO[CH2:28][CH2:29]O>>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][CH:19]2[N:25]3[CH2:22][CH2:23][CH:24]2[CH2:28][CH2:29]3)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CC2CCC1N2
Reactant: COCCO
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Product: N#CC(CCC1C2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
15 Parts of 2,2-diphenyl-4-bromobutyronitrile are condensed with 12.9 parts of 7-azabicyclo[2. 2. 1]heptane by reflux in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture is cooled and extracted with dilute hydrochloric acid. The aqueous hydrochloric acid extract is made basic with sodium hydroxide solution and extracted with ether. The ether extracts are dried over anhydrous sodium sulfate. Filtration and removal of the ether by evaporation at reduced pressure provides 2,2-diphenyl-4-(4-azabicyclo[2. 2. 1]hept-7-yl)butyronitrile, melting at 79°-81° C. 4.9 Parts of this butyronitrile, 1.5 parts of sodium azide, 1.2 parts of ammonium chloride, and 0.023 parts of lithium chloride are placed in 50 parts by volume of dimethylformamide and heated at 125° C for 12 hours. The mixture is cooled and the solid is filtered from the dimethylformamide. The solid is washed with dimethylformamide and water. The dried solid is 5-[1,1-diphenyl-3-(7-azabicyclo[2. 2. 1]hept-7-yl)]propyl-1H-tetrazole, melting at 284°-286° C.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 1-(4-chlorophenyl)piperazine (172.5 mg, 0.88 mmol, 5.00 equiv), and DIEA (170.3 mg, 1.32 mmol, 3.00 equiv) in DMF (4 mL) was placed in a 8-mL sealed tube, stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:50)) afforded 153.4 mg (69%) of methyl 3-(4-(4-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]#[N:33])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]#[N:33])[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCN1CCC(N)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#CCCN1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.35 g, 45.5 mmol), 3-(4-amino-piperidin-1-yl)-propionitrile (hydrochloride salt) (9.48 g, 50.0 mmol), diisopropylethylamine (24.5 ml, 141 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 18 h. The mixture was cooled to 25° C. and was concentrated to approximately 40 ml volume. This material was partitioned between water (2000 ml) and CH2Cl2 (3×2000 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 6% CH3OH in CH2Cl2) afforded 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (19.3 g, 93% over 3 steps) as a yellow-orange foam. LCMS (Method G, ESI): RT=0.69 min, m+H=455.3. This material was used in the next step below without additional characterization.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.NN.[NH:16]([C:18]1N=CC(C2C=NC=CC=2)=CC=1)[NH2:17]>N1C=CC=CC=1.C(OCC)(OCC)OCC.C(O)(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]3[N:7]([CH:18]=[N:16][N:17]=3)[CH:6]=2)[CH:9]=1
Reactant: NNc1ccc(-c2cccnc2)cn1
Reactant: Clc1ccc(-c2cccnc2)cn1
Agent: NN
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CCOC(OCC)OCC
Product: c1cncc(-c2ccc3nncn3c2)c1

Procedure:
As described in Example 5, 2.2 g of 6-chloro-3,3'-bipyridine was treated with 3.6 ml of anhydrous hydrazine in pyridine at 115° C. for 48 hours. The resulting crude 6-hydrazino-3,3'-bipyridine was dissolved in 25 ml of triethyl orthoformate and 2 drops of acetic acid and heated to 130° C. for 10 hours. The volatiles were removed at reduced pressure and the residue purified by chromatography on silica gel, eluting with ethyl acetate:methanol (9:2). The obtained solid was recrystallized from ethyl acetate-methanol, giving the desired product, mp 200°-202.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cccc(F)c4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: [CH3:1][C:2]12[C:9](=[O:10])[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[CH3:12][Li].O>COC.C(OCC)C>[CH3:11][C:6]12[C:9]([CH3:12])([OH:10])[C:2]([CH3:1])([CH2:8][CH2:7]1)[CH2:3][CH2:4][CH2:5]2
Reactant: [Li]C
Reactant: CC12CCCC(C)(CC1)C2=O
Agent: COC
Solvent: O
Solvent: CCOCC
Product: CC12CCCC(C)(CC1)C2(C)O
Yield: 73.3 %

Procedure:
To a solution of 45,8 g (0,3 mole) of 1,5-dimethyl-bicyclo[3.2.1]octane-8-one in 150 ml dried dimethylether at boiling temperature 250 ml (178 g) of a 5% solution of methyl lithium (4 mole) in diethylether were dropwise added under stirring. After 1 h of stirring at boiling temperature about 50 ml water were dripped in followed by extraction with diethylether. The combined organic phases were dried over Na2SO4, evaporated under vacuum and distilled which resulted in 37 g (73%) of 8 in form of a colorless oil having a boiling point (1 mm) of 74° C. IR (as oil film): 3500 cm-1 (O--H).--NMR (CCl4): δ=0,87, s, 6H (1,5-CH3), 1,05, s, 3H (8-CH3) 1.5 ppm, br.s, 4H (6,7-CH2).--MS: m/e (%)=168 (33, M+), 153 (28), 150 (29). 135 (46), 125 (30), 124 (18), 123 (31, 122 (20), 121 (42), 111 (11), 110 (10), 109 (16), 108 (19), 107 (85), . . . , 43 (100).C11H20O (M=168,27).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:16])[CH:10]=2)[N:5]=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.O.[CH3:24]N(C)C=O>>[CH:17]1([C:20]([O:15][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:16])[CH:10]=3)[N:5]=[C:4]([CH2:3][CH3:24])[C:13]=2[CH3:14])=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: CC1=Nc2ccc(F)cc2C(=O)C1C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCc1nc2ccc(F)cc2c(OC(=O)C2CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 180 mg of sodium hydride in 10 ml of dimethylformamide was added 923 mg of 2-methyl-6-fluoro-3-methyl-4-quinolone on an ice bath, and the solution was stirred at room temperature for 15 min. After the solution was cooled on an ice bath, and 470 mg of cyclopropanecarbonyl chloride was added to the solution, and the mixture was stirred at room temperature for 4 hours. The mixture was poured into 20 ml of water. The solution was extracted with chloroform, and the chloroform solution was washed with water, dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product thus obtained was purified by silica gel column chromatography (Wako Gel C-200, n-hexane:ethyl acetate=7:1) to give 1.02 g of 4-cyclopropanecarbonyloxy-2-ethyl-6-fluoro-3-methylquinoline.
Reaction SMILES: [CH:1]([C:3]1[C@H:12]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C@@H:11]([OH:25])[C:10]2[C:5](=[CH:6][C:7]3[O:28][CH2:27][O:26][C:8]=3[CH:9]=2)[CH:4]=1)=[O:2].N1[CH:33]=[CH:32]N=C1.[O-]Cl=O.[Na+].[OH2:38]>CN(C=O)C>[CH2:27]1[O:28][C:7]2[CH:6]=[C:5]3[C:10]([C@H:11]([O:25][Si:15]([CH2:32][CH3:33])([CH2:19][CH3:20])[CH2:16][CH3:17])[C@@H:12]([CH2:13][O:14][Si:15]([CH:16]([CH3:18])[CH3:17])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[C:3]([C:1]([OH:38])=[O:2])=[CH:4]3)=[CH:9][C:8]=2[O:26]1
Reactant: c1c[nH]cn1
Reactant: CC(C)[Si](OC[C@H]1C(C=O)=Cc2cc3c(cc2[C@@H]1O)OCO3)(C(C)C)C(C)C
Reactant: O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H]1c2cc3c(cc2C=C(C(=O)O)[C@@H]1CO[Si](C(C)C)(C(C)C)C(C)C)OCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of aldehyde 11 (900 mg, 2.25 mmol) in DMF (20 mL) was added TESCI (715 JtL, 3.38 mmol) and imidazole (460 mg, 6.75 mmol) at 0° C. and the reaction mixture was allowed to warm to r.t. overnight. Water was added and the product was extracted with Et20, the organic layer dried over MgSO4 and evaporated. The residue was then dissolved in t-BuOH (40 mL) and 2-methyl-2-butene (12 mL). A solution of NaClO2 (1.81 g, 20 mmol) and NaH2PO4 (1.93 g) in water (20 mL) was added and the mixture was stirred overnight. The product was extracted with Et2O, dried over MgSO4, concentrated and purified by silica gel column chromatography (10-30% EtOAc in hexanes) to give the acid 12 as a white powder (1.02 g, 85% over 2 steps). 1H NMR (400 MHz, CDCl3) 00.65 (q, J=8.0 Hz, 6H), 0.94 (t, J=8.0 Hz, 9H), 1.06 (m, 21H), 3.05, (apt t, J=10 Hz, 1H), 3.34 (ddd, J=10.0, 4.5, 1.6 Hz, 1H), 3.77 (dd, J=10.0, 4.5 Hz, 1H), 5.03 (s, 1H), 6.03 (s, 2H), 6.81 (d, J=4.8 Hz, 2H), 7.67 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[S:26][C:25]=1[C:35]([NH2:37])=[O:36]>C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:23][C:24]3[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:26][C:25]=3[C:35](=[O:36])[NH:37]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
To a stirred solution of 1-acetyl-4-piperidone (0.130 g, 0.920 mmol) and p-toluenesulfonic acid monohydrate (0.004 g, 0.02 mmol) in acetic acid (4 mL) was added 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.050 g, 0.23 mmol). The mixture was heated at 80° C. for 5 h. Then, the reaction was allowed to cool to room temperature and concentrated. The obtained residue was dissolved in methanol (25 mL) and the solution was stirred with solid NaHCO3 (1.5 g) for 20 min. Then, the solution was filtered, and the filtrate was concentrated. The obtained residue was triturated with H2O. The obtained yellow solid was triturated with hot ethyl acetate to give the title compound (0.0407 g, 52%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]2[CH:18]=O.Cl.Cl.[NH:22]1[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=[CH:23]1.C([BH3-])#[N:31].[Na+]>CO>[NH2:29][C:27]([C:26]1[NH:22][CH:23]=[N:24][C:25]=1[NH:31][CH2:18][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[N:7]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:6]=1)=[O:28]
Reactant: [BH3-]C#N
Reactant: NC(=O)c1cnc[nH]1
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2cc(Cl)ccc21
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2cc(Cl)ccc21
Reaction time: 19 h
Yield: 25.7 %

Procedure:
A mixture of tert-butyl 5-chloro-3-formyl-1H-indole-1-carboxylate (0.84 g, 3.0 mmol, obtained from Example 10(a)), 1H-imidazole-5-carboxamide dihydrochloride (0.49 g, 3.0 mmol) and sodium cyanoborohydride (0.45 g, 7.2 mmol) in MeOH (5 mL) was stirred at r.t for 19 h. The reaction mixture was partitioned between H2O (25 mL) and CHCl3 (3×25 mL), the combined organic phases were dried over MgSO4 and evaporated. Purification by flash chromatography on silica using a gradient of methanol (2-8%) in chloroform gave the title compound (0.30 g, 26%). MS (ESI) m/z 390 (M+1).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:4]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:4]1)=[N+:22]=[N-:23]
Reactant: Clc1ccc(C2CC(CBr)Cc3ccccc32)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Referring to Scheme 2, acylation of the alpha-tetralone 4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalen-1-one (Compound 1) with diethylcarbonate was followed by reduction with triethylsilane to give 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid ethyl ester (Compound 10). Reduction and conversion to 3-bromomethyl-1-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalene (Compound 12) is followed by alkylation with sodium azide in DMF to give 3-azidomethyl-1-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalene (Compound 13). Chiral separation of Compound 13 is followed by hydrogenation to give a compound of the invention, C-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-methylamine (Compound 14). Alternatively, reduction and conversion to 3-bromomethyl-1-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalene (Compound 12) is followed by alkylation with substituted amines to give 1-phenyl-3-aminoalkyl-1,2,3,4-tetrahydronaphthalenes (Compound 15).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].[CH:13](Br)([CH3:15])[CH3:14]>>[Cl:1][C:2]1[C:10]([O:11][CH:2]([CH3:10])[CH3:3])=[CH:9][C:5]([C:6]([O:8][CH:13]([CH3:15])[CH3:14])=[O:7])=[CH:4][C:3]=1[O:12][CH:5]([CH3:6])[CH3:4]
Reactant: CC(C)Br
Reactant: O=C(O)c1cc(O)c(Cl)c(O)c1
Product: CC(C)OC(=O)c1cc(OC(C)C)c(Cl)c(OC(C)C)c1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Isopropyl 4-chloro-3,5-diisopropoxybenzoate (4) (43 mg, 0.12 mmol) was prepared from 4-chloro-3,5-dihydroxybenzoic acid (3) (72 mg, 0.38 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that isopropyl bromide (8 eq.) was used instead of cyclopentyl bromide and the mixture was stirred at 50° C. for 20 h: 1H NMR (400 MHz, CDCl3) δ: 7.25 (2H, s), 5.23 (1H, sep), 4.63 (2H, sep), 1.38 (18H, m).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[CH:28](OCC)(OCC)OCC>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:19]([C:20]4[O:21][CH:28]=[N:23][N:22]=4)[CH:18]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1
Reactant: CCOC(OCC)OCC
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnco3)c1)C2=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (200 mg, 0.52 mmol) obtained in Step 2 was suspended in triethyl orthoformate (10 mL), and the mixture was stirred at 100° C. for 24 hours. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(1,3,4-oxadiazol-2-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (165 mg, 80%).
Reaction SMILES: [Cl-:1].[Ce+3].[Cl-].[Cl-].[I-].[Na+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[CH2:22]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[ClH:1].[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]([CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)([OH:35])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(CBr)c1ccc(N2CCCC2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [Cl-]
Agent: [Ce+3]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(CC1(O)CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Reaction time: 2 h
Yield: 39.2 %

Procedure:
Anhydrous cerium chloride (0.99 g, 4.0 mmol) and sodium iodide (1.8 g, 12.0 mmol) are added to 10 ml of anhydrous tetrahydrofuran as a solvent to form a suspension. Dissolving 1.07 g (4.0 mmol) of 2-bromo-1-(4-(pyrrolidin-1-yl)phenyl)ethanone and 0.76 g (4.0 mmol) of N-benzyl-4-piperidone into 10 ml of anhydrous tetrahydrofuran, and the solution is added dropwise to the above suspension and reacting at room temperature for 2 hours. Operating according to the post-treatment procedure in General Method three to obtain 0.65 g of a white crystal, with yield of 34.6%.