Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].C1(C)C=CC(S(O[C@H:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)(=O)=O)=CC=1>C(O)C>[CH2:18]([N:15]1[CH2:16][CH2:17][C@H:13]([CH2:1][NH2:2])[CH2:14]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Solvent: CCO
Product: NC[C@H]1CCN(Cc2ccccc2)C1
Temperature: 140 °C
Reaction time: 0.08 h

Procedure:
An autoclave is initially charged with 6.20 ml of methylamine solution in ethanol and a solution of 2.000 g of (S)-1-benzylpyrrolidin-3-yl toluene-4-sulphonate in 2 ml of ethanol. The reaction solution is subsequently heated to 140° C. over 15 hours. The reaction solution is cooled to room temperature and concentrated to dryness, and the residue is taken up in 10 ml of water. The aqueous solution is extracted with dichloromethane (2×10 ml). The aqueous phase is then admixed with 1 g of potassium carbonate and the suspension is stirred at room temperature over 5 minutes. The solid is filtered off and the filtrate is extracted with dichloromethane (2×10 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The residue is purified by means of flash chromatography (SiO2 60F). The title compound is obtained as a yellow oil. Rf=0.14 (200:20:1 dichloromethane-methanol-25% conc. ammonia).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[C:23](OCC)(=O)[CH3:24]>>[ClH:20].[CH2:23]([C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[CH:18]=1)[CH3:24]
Reactant: CCOC(C)=O
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: Cl
Product: CCc1cc(C)cnc1N1CCNCC1

Procedure:
By reaction and treatment in the same manner as in Example 53 and using 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g), which is the intermediate described in Preparation Example 48, a compound was obtained, which was treated with 4N hydrogen chloride/ethyl acetate (2 mL) to give the title compound (1.1 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>O1CCCC1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: CC(C)C(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (1.3 mL, 8.9 mmol) in tetrahydrofuran (25 mL) at 78° C. was added n-BuLi (2.2M in hexanes, 4.1 mL, 8.9 mmol). The reaction mixture was warmed to 0° C. and after 10 min was re-cooled to 78° C. and aripiprazole (2.0 g, 4.5 mmol) added. The reaction mixture was stirred for 30 min and then isobutyryl chloride (0.7 mL, 6.7 mmol) added. After 2 h the reaction mixture was warmed to room temperature and stirred for 1 h. A second reaction was carried out under exactly the same conditions and the two reactions were combined. This mixture was washed with water, dried over MgSO4, filtered and evaporated. The residue was dissolved in diethyl ether and 4M HCl in diethyl ether added to form a precipitate. The mother liquor was decanted and the residual gum was washed with diethyl ether. The gum was then partitioned between ethyl acetate and saturated sodium bicarbonate, and the organic layer separated. After drying over MgSO4 and evaporation, the residue was further purified on silica eluting with 1:1:0.1 dichloromethane/ethyl acetate/methanol to give Compound-16 (1.3 g) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>ClCCl>[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7]1
Reactant: CC1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC1CN(C(=O)OCc2ccccc2)CCN1
Reaction time: 1 h

Procedure:
A 4 g portion of 2-methylpiperazine was dissolved in 40 ml of dichloromethane, and 1.71 g of benzyl chloroformate was added dropwise thereto at −78° C. After 1 hour of stirring, the mixture was washed by adding water and dried and then the solvent was evaporated to obtain 2.0 g of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([SH:22])[N:17]=[C:16]([NH2:23])[C:15]=2[C:24]#[N:25])[CH2:10][CH2:9]1)(=[O:3])[CH3:2].Cl[CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[S:31][CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[S:31][CH:32]=3)[N:17]=[C:16]([NH2:23])[C:15]=2[C:24]#[N:25])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CC(=O)OCCCN1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCN1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.16 mmol) of the compound from Example 29A are dissolved in 3 ml of dry DMF, and 46 mg (0.19 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 53 mg (0.63 mmol) of sodium bicarbonate are added in succession. The reaction mixture is stirred at RT for 8 h. After removal of the solvent on a rotary evaporator the residue is directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH:7]=[CH2:8])[C:3](=[O:5])[CH3:4].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].OCC(CO)O.[Cl-].N>O1CCCC1>[CH3:4][C:3]([OH:5])([CH:2]([CH3:1])[CH2:6][CH:7]=[CH2:8])[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: C=CCC(C)C(C)=O
Reactant: COC(=O)CBr
Agent: N
Agent: [Cl-]
Solvent: OCC(O)CO
Solvent: C1CCOC1
Product: C=CCC(C)C(C)(O)CC(=O)OC
Temperature: 25 °C

Procedure:
3-Methyl-5-hexen-2-one (J. Chem. Soc., Chem. Comm. 19, 1991, 1399) (17 g, 106 mmol) and methyl bromoacetate (24.4 g, 159 mmol) were dissolved in tetrahydrofuran (100 mL), and the solution was added dropwise to a tetrahydrofuran (50 mL) (zinc (10.4 g, 159 mmol) and trimethyl borate (30 mL)) solution under reflux. After reflux for 3 hours, the mixture was cooled to room temperature, and glycerin (30 mL) and a saturated aqueous solution of ammonia chloride (100 mL) were added thereto, followed by two extractions with ethyl acetate. The ethyl acetate layer was washed with saturated saline, then dried, and then concentrated. The residue was purified by silica gel column chromatography (200 g) to obtain the compound of interest as an oil substance (11.7 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.S(Cl)(Cl)=O.[CH3:17]N(C=O)C.Cl>C(Cl)Cl.CO>[CH3:17][O:7][C:6](=[O:8])[C:5]1[C:4]([F:12])=[CH:3][C:2]([Br:1])=[CH:10][C:9]=1[F:11]
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-Bromo-2,6-difluoro-benzoic acid (5 g, 21 mmol) in DCM (10 mL) is added thionyl chloride (15 mL) and DMF (0.5 mL). The mixture is stirred at room temperature for 2.5 h. It is then cooled to 0° C. and MeOH (20 mL) is added carefully causing vigorous HCl evolution. After stirring for an additional 0.5 h, the clear solution is partitioned between DCM (50 mL) and water (50 mL). The organic layer is washed with saturated NaHCO3, brine, dried over MgSO4 and the solvent is removed under vacuum to afford the title compound as a pale yellow oil which is used without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH2:12])=[N:7]2.Br[C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][OH:28])[CH:23]=[CH:24][CH:25]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][OH:28])[CH:23]=[CH:24][CH:25]=1)=[N:7]2
Reactant: OCCc1cccc(Br)c1
Reactant: Cc1nc(-c2ccccc2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2)n2nc(Nc3cccc(CCO)c3)ncc12
Temperature: 160 °C
Yield: 28.1 %

Procedure:
To a mixture of 5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine hydrochloride (0.026 g, 0.10 mmol), 2-(3-bromophenyl)ethanol (0.022 g, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (2.7 mg, 0.0030 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5.6 mg, 0.0090 mmol) and sodium t-butoxide (0.025 g, 0.23 mmol) was added dioxane (1 mL). The solution was heated with microwave radiation to 160° C. for 15 minutes. After cooling to room temperature, the solution was filtered, and silica gel (1 g) was added, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (50:50) to ethyl acetate:hexanes (100:0) using a RediSep silica gel cartridge (4 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 2-{3-[(5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-yl)amino]phenyl}ethanol (0.0097 g) as a yellow solid. 1H NMR (CDCl3): δ8.75 (s, 1H), 8.51-8.45 (m, 2H), 7.74 (s, 1H), 7.56-7.26 (m, 5H), 7.04-6.95 (m, 2H), 3.91 (t, J=6.4 Hz, 2H), 2.92 (t, J=6.4 Hz, 2H), 2.59 (s, 3H). MS m/z 346 (M+1).
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].Cl.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]4[C:25]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31][C:26]=5[N:27]([CH3:30])[C:28]=4[CH:29]=3)[C:17](=[O:36])[CH:16]=2)=[N:11][CH:12]=1.CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:33]1[CH2:34][CH2:35][C:25]2[C:24]3[CH:23]=[CH:22][C:21]([N:18]4[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:10]5[CH:9]=[CH:8][C:7]([F:6])=[CH:12][N:11]=5)=[CH:16][C:17]4=[O:36])=[CH:29][C:28]=3[N:27]([CH3:30])[C:26]=2[CH2:31][CH2:32]1)(=[O:2])[CH3:3]
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CCNCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2c(n(C)c3cc(-n4ccc(OCc5ccc(F)cn5)cc4=O)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
AcCl (0.01 mL, 0.2 mmol) was added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (49 mg, 0.11 mmol), DMAP (3 mg, 0.03 mmol), and Et3N (0.03 mL, 0.3 mmol) in CH2Cl2 (10 mL) under N2, and the resulting solution was stirred at 25° C. for 4 h. H2O was added and the resulting phases were separated. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded 39 mg (78%) of the title compound as a white solid as a mixture of rotomers: mp 88-94° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.0 Hz, 1H), 7.84 (ddd, J=9.0, 9.0, 3.0 Hz, 1H), 7.66 (dd, J=8.5, 4.5 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.38 (dd, J=3.0, 1.5 Hz, 1H), 6.92-6.88 (m, 1H), 6.12 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.22 (s, 2H), 3.82-3.76 (m, 2H), 3.75-3.63 (m, 5H), 3.10 (t J=5.5, 1H), 3.05-2.98 (m, 2H), 2.93 (t, J=5.5, 1H), 2.13 (s, 1.5H), 2.08 (s, 1.5H); ESI MS m/z 461 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][N:15]1[C:27]2[C:18](=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]([CH3:28])[NH:22][CH2:21][CH2:20]3)[CH:17]=[CH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:27]5[N:15]([CH3:14])[CH:16]=[CH:17][C:18]5=4)[CH:23]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1ccc1c2ccn1C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc3c(ccn3C)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3,6-Dimethyl-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([C:25]4[O:26][C:27]([C:30]5[N:35]=[C:34]([C:36]([O:38]C)=[O:37])[CH:33]=[CH:32][CH:31]=5)=[CH:28][N:29]=4)=[O:24])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([C:25]4[O:26][C:27]([C:30]5[N:35]=[C:34]([C:36]([OH:38])=[O:37])[CH:33]=[CH:32][CH:31]=5)=[CH:28][N:29]=4)=[O:24])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCN(C)CC5)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc(-c3ccc(CCC(=O)c4ncc(-c5cccc(C(=O)O)n5)o4)cc3)cc2)CC1
Yield: 20.6 %

Procedure:
Methyl 6-(2-(3-(4′-((4-methylpiperazin-1-yl)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (10 mg, 0.019 mmol) was dissolved in THF/H2O (3:2, 2 mL) and LiOH (1 mg, 0.06 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 40 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4′-((4-methylpiperazin-1-yl)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a white solid (2 mg, 21%): 1H NMR (CDCl3, 600 MHz) δ 8.17 (s, 1H), 7.93 (s, 3H), 7.48 (d, 2H, J=7.8 Hz), 7.44 (d, 2H, J=7.8 Hz), 7.31-7.27 (m, 4H), 3.68 (s, 2H), 3.47 (t, 2H, J=6.9 Hz), 3.15 (t, 2H, J=6.9 Hz), 2.82 (bs, 4H), 2.69 (s, 3H), 2.10-2.00 (m, 4H); HR ESI-TOF m/z 511.2334 (M+H+, C30H30N4O4, requires 511.2340).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][N:3]=1.Br[CH2:14][CH2:15]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cc1ccc(Cl)nc1
Reactant: BrCCBr
Product: CS(=O)(=O)C1(c2ccc(Cl)nc2)CC1
Yield: 52 %

Procedure:
The title compound was prepared from 2-chloro-5-methanesulfonylmethyl-pyridine and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 52% of theory; Mass spectrum (ESI+): m/z=232/234 (Cl) [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:10]([N+:24]([O-:26])=[O:25])[CH:9]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[CH2:27]([O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:10]([N+:24]([O-:26])=[O:25])[CH:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1c([N+](=O)[O-])cc(OCc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Anhydrous K2CO3 (0.50 g, 3.68 mmol) was added to a solution of ethyl 2-[4-hydroxy-2-nitronaphthalen-1-yl]acetate (0.42 g, 1.53 mmol) and benzyl bromide (0.44 mL, 3.68 mmol) in acetone (4 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with AcOEt (50 mL), and to the mixture was added N-methypiperazine (3 mL) to remove any excess benzyl bromide. The mixture was washed with water (10 mL), 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL), and then dried (Na2SO4) and evaporated to yield ethyl 2-[4-benzyloxy-2-nitronaphthalen-1-yl]acetate (0.35 g, 63%) as a yellow solid. Mp 128-130° C.; 1H NMR (CDCl3, 500 MHz) δ 8.44 (dd, 0.5, 8.0, 1H), 8.10 (d, 8.5, 1H), 7.71 (t, 7.0, 1H), 7.66 (t, 7.0, 1H), 7.54 (d, 7.0, 2H), 7.46 (t, 7.5, 2H), 7.43 (s, 1H), 7.40 (t, 7.0, 1H), 5.32 (s, 2H), 4.33 (s, 2H), 4.21 (q, 7.0, 2H), 1.27 (t, 7.0, 3H); EIMS m/z 365 (M+); IR (neat) νmax 2980, 1725, 1592, 1524, 1512, 1469, 1451, 1426, 1371, 1331, 1252, 1202, 1159, 1111, 1022, 842, 770, 756, 724, 690 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH3:31][Zn]C>C1(C)C=CC=CC=1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4]([CH3:31])[CH:3]=1
Reactant: C[Zn]C
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc2c1C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans tert-butyl 6-methyl-5-oxo-8-(trifluoromethylsulfonyloxy)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 91, Part A (225 mg, 0.5 mmol) was added dimethylzinc (0.75 mL of a 2.0 M solution in toluene, 1.5 mmol). The reaction mixture was degassed with a stream of argon and then there was added bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (18 mg, 0.025 mmol). The reaction mixture was allowed to stir at 65° C. for 18 h. The reaction was allowed to cool to ambient temperature and was quenched with 1N HCl. The mixture was diluted with ethyl acetate and the organics were washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 0.18 g of the title compound as an off-white solid, which was sufficiently pure to be employed directly in Part B. LRMS (ESI): 317.3 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1
Yield: 90 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (90%).
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:9]=1.C(Cl)(=O)C(C)(C)C.Br.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37](=[O:41])[CH2:38][NH:39][CH3:40])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>ClCCl>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37](=[O:41])[CH2:38][N:39]([CH3:40])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: CNCC(=O)c1ccc(OC)c(OC)c1
Reactant: O=C(O)/C=C/c1cccnc1
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)CN(C)C(=O)/C=C/c2cccnc2)cc1OC
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
Dichloromethane (50 ml) and triethylamine (2.69 ml, 19.30 mmol) were sequentially added to trans-3-(3-pyridyl)acrylic acid (1.44 g, 9.65 mmol) and stirred for 10 minutes. Then, pivaloyl chloride (1.18 ml, 9.65 mmol) was added and stirred for 13 minutes. 1-(3,4-Dimethoxyphenyl)-2-(methylamino)ethanone hydrobromide (2.79 g, 9.65 mmol) was dissolved in dichloromethane (4 ml) and triethylamine (1.34 ml, 9.65 mmol), added to the reaction mixture and stirred at room temperature for 30 minutes. After the reaction mixture was washed with water and aqueous saturated sodium bicarbonate solution, the organic phase was dried over magnesium sulfate and the solvent was distilled out under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to yield a crude product. The crude product was recrystallized to yield the titled compound (1.84 g, 5.41 mmol, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([CH:22]=1)[C:7]([CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:8].[ClH:24]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:7]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[O:8])[CH:22]=1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Cl)ccc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cc(Cl)ccc1F)C1CCNCC1
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-(5-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (287.9 mg, 0.843 mmol) in dioxane (2.41 mL) was treated with HCl (2.11 mL, 8.43 mmol) at rt and the resulting reaction mixture was stirred overnight. The reaction mixture was diluted with hexanes and filtered by suction to afford (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone as its HCl salt (146 mg, 62.3%) as a yellow solid. ESI-MS m/z [M+H]+242.20.