Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:34](=[O:35])[C:13]2=[CH:14][N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]2=[N:11]1)(=[O:3])[CH3:2].[CH3:36][Mg]Br.C(=O)(O)[O-].[Na+].O>ClCCl>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:34](=[O:35])[C:13]2=[CH:14][N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]2=[N:11]1)([CH3:36])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(2-acetylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 532, 77 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL) and cooled to −78° C. Methylmagnesium bromide (0.056 mL, 3 M diethyl ether solution, 0.17 mmol, 1 equiv) was added dropwise and the mixture was stirred for 30 minutes at −78° C. Additional methylmagnesium bromide (0.057 mL, 3 M diethyl ether solution, 0.17 mmol, 1 equiv) was added and the mixture was stirred for an additional 30 minutes at −78° C. The mixture was treated with sodium bicarbonate (3 mL, aqueous saturated), warmed to ambient temperature, poured into water and extracted with dichloromethane (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 0:100 hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.12 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.15 (1H, dd, J=8.0, 1.1 Hz), 7.90 (1H, dd, J=7.9, 1.3 Hz), 7.84 (2H, d, J=8.7 Hz), 7.78 (1H, d, J=8.6 Hz), 7.73 (1H, d, J=1.4 Hz), 7.64-7.60 (1H, m), 7.53 (1H, t, J=7.6 Hz), 7.48 (2H, d, J=8.7 Hz), 7.46-7.43 (1H, m), 7.35 (1H, td, J=7.5, 1.3 Hz), 7.17 (1H, dd, J=7.5, 1.1 Hz), 6.53 (1H, dd, J=2.3, 1.9 Hz), 5.77 (2H, s), 5.28 (1H, s), 1.37 (6H, s) ppm; high resolution mass spectrometry (ES+) m/z 476.2069 [(M+H)+; calculated for C29H26N5O2: 476.2081].
Reaction SMILES: [CH2:1]([P:5]([CH2:21][CH2:22][CH2:23][CH3:24])[O:6]C1C=CC(C(C)(C)C)=CC=1C(C)(C)C)[CH2:2][CH2:3][CH3:4].O>C(#N)C>[CH2:1]([PH:5](=[O:6])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCP(CCCC)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Solvent: O
Solvent: CC#N
Product: CCCC[PH](=O)CCCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
35 g (0.1 mol) of 2.4-di-tert.-butylphenyl dibutylphosphinite from Example 5 were reacted in 100 ml of acetonitrile with 2.0 g (0.11 mol) of water at 20° C., and the mixture was then stirred at 70° C. for 1 hour. The solvent was distilled off in vacuo, 50 ml of water and 100 ml of ethyl acetate were added, the phases were separated, and the organic phase was extracted two more times with 50 ml each of water. The combined aqueous phases were evaporated, and the residue distilled in vacuo, giving 10.2 g (70%) of a colorless liquid having a boiling point of 102° to 104° C./0.25 mbar.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1C=CC=CC=1>[CH3:1][N:2]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)N(C)c1ccccc1
Yield: 54.4 %

Procedure:
N-methylaniline (15.1 g), diethyl bromomalonate (16.9 g) and dry benzene (90 ml) were mixed and heated under reflux for 16 hours with stirring. The reaction mixture was washed, dried and concentrated by the same procedure as in Example 2, (1). The residue was purified by silica gel column chromatography using benzene/hexane (2:1) as an eluent to give 10.2 g (yield 54%) of diethyl N-methylanilinomalonate having the following NMR data.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])(=O)=O.CN(C)P(N(C)C)(N(C)C)=O.O>C(O)C>[O:21]([CH:19]([CH3:20])[CH2:18][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(COS(C)(=O)=O)Oc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Product: CC(CNc1ccc(C(=O)O)cc1)Oc1ccccc1
Temperature: 125 °C

Procedure:
A mixture of 33 g of ethyl p-aminobenzoate, 0.10 mole of 2-phenoxy-1-propanol O-methanesulfonate and 80 ml of hexamethylphosphoramide is heated at 125° C. for 18 hours. The mixture is chilled, poured into water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated under vacuum to an oil. The oil is combined with 250 ml of ethanol-water (9:1) and 20 g of potassium hydroxide and the mixture refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with water and extracted with chloroform. The chloroform extracts are washed with water, dried (magnesium sulfate) and concentrated under vacuum to give an oil. Ethanol is added and the mixture chilled and filtered to give the product, mp 140°-144° C. Recrystallization gives the product as crystals, mp 145°-147° C.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[Br:2][C:3]1[C:4]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Nc2ncc(Br)c(NC(C)C)n2)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)Nc1nc(Nc2ccc(S(C)=O)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.77 g (4.6 mmol) of 5-bromo-N4-isopropyl-N2-[4-(methylsulfanyl)phenyl)-pyrimidine-2,4-diamine hydrochloride is taken up in 40 ml of DCM and mixed with 1.73 g (5.5 mmol) of 3-chloroperoxybenzoic acid (55%). The batch is stirred for 90 minutes at room temperature and then diluted with DCM. It is washed with saturated NaHCO3 solution and saturated NaCl solution. The organic phase is dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 9:1). 553 mg (1.5 mmol, corresponding to 33% of theory) of the product is obtained.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:10][CH2:9][C:8]([CH3:11])([CH3:12])[C:7]([NH:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:13]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)(CO)C(=O)NC1CCCC1
Product: CC(C)(COc1cccc(N)c1C#N)C(=O)NC1CCCC1

Procedure:
Prepared as in Example 22b from N-cyclopentyl-3-hydroxy-2,2-dimethylpropanamide (Example 29c) and 2-amino-6-fluorobenzonitrile as a white solid (45%). 1H NR (400 MHz, DMSO-d6) δ 1.19 (s, 6H), 1.40-1.49 (m, 4H), 1.61-1.63 (m, 2H), 1.74-1.79 (m, 2H), 3.95 (s, 2H), 4.03 (m, 1H), 5.98 (s, 2H), 6.19 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H). MS 302 (MH+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:1]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CNCC3)nc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CN(Cc2ccccc2)CC3)nc1
Yield: 25.7 %

Procedure:
Combine 6-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide (94 mg, 0.35 mmol), benzaldehyde (37 μL, 0.37 mmol), sodium triacetoxyborohydride (96 mg 0.46 mmol), acetic acid (21 μL, 0.37 mmol), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with 5% methanol in dichloromethane (3×25 mL). Dry the combined 5% methanol in dichloromethane extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 100 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform to yield 6-(2-benzyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide 2039910 (30 mg, 0.09 mmol): m/z=360.12 (M+1); 1H NMR (CDCl3, 300.00 MHz): 8.50 (d, 1H); 8.09-8.05 (m, 1H); 7.34-7.20 (m, 5H); 7.09 (d, 1H); 6.87-6.82 (m, 2H); 6.71 (d, 1H); 5.80 (s, 2H); 3.63-3.57 (m, 4H); 2.87-2.69 (m, 4H), HPLC=96%@2.98 m (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][S:12][C:11]3=[N:14][CH:15]=[C:16]([C:17]([O:19]CC)=[O:18])[N:10]23)=[CH:5][CH:4]=1)#[N:2].C(Cl)[Cl:23].[OH-].[Na+]>C(O)C>[ClH:23].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][S:12][C:11]3=[N:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[N:10]23)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2n1C(c1ccc(C#N)cc1)CS2
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1
Reaction time: 16 h

Procedure:
To a solution of the ester from Step C (4.81 g, 16.1 mmol) in ethanol (10 mL)/methylene chloride (10 mL) at 0° C. was added sodium hydroxide (10 M in water, 2.09 mL, 20.9 mmol). After stirring for 16 hours, the organic solvents were evaporated in vacuo at 25° C., and the water removed by a stream of nitrogen. The crude product was acidified by the addition of hydrogen chloride (1 M in diethylether, 40 mL) and reconcentrated to provide the crude product as a white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][C:14]=3SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:27][S:28]([O-:30])=O.[K+].[CH3:32]O>O>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][C:14]=3[S:28]([CH3:32])(=[O:30])=[O:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CO
Reactant: CCc1cc(SC)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C2=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCc1cc2c(c(S(C)(=O)=O)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 4 h
Yield: 84 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-ethyl-7-methylthio-pyrazino[2,1-a]isoindol-6(2H)-one (42 mg, 0.12 mmol) in dry MeOH (0.75 mL) and water (0.75 mL) was added oxone (93 mg, 0.15 mmol). The reaction was stirred for 4 h and then diluted with water. The reaction was extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0–50% EtOAc in hexanes) to yield 38 mg (84%) of the product as a colorless oil. MS (ESI) 395 (M+H).
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[Cl:13]>CO.[OH-].[OH-].[Pd+2]>[ClH:13].[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([NH2:9])[CH:8]=1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Oc1ccc(F)c(N)c1
Product: Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 85.6 %

Procedure:
To a solution (20 mL) of 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (1.00 g, 4.0 mmol) in methanol was added 20% palladium hydroxide on carbon (0.4 g) under a nitrogen atmosphere. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 days. After nitrogen replacement, the catalyst was filtered off. The solvent was evaporated from the filtrate under reduced pressure, and the residue was recrystallized from diethyl ether to give the title compound (759 mg, 86%) as a pale-green powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22]C#N)[CH:19]=[CH:20][CH:21]=1.[OH-].[Na+].[CH2:27](O)[CH3:28]>CO>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[O:3][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4([C:28]5[CH:27]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=5)[O:14][CH2:13][CH2:12][O:11]4)=[CH:6][C:5]=23)[CH:19]=[CH:20][CH:21]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(C2OCCO2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(C2(c3ccc4noc(-c5cccc(Cl)c5)c4c3)OCCO2)cc1
Yield: 86 %

Procedure:
Interm. (7-a) (50 g) and then (3-chlorophenyl)acetonitrile (34.8 ml) were added to a mixture of sodium hydroxide (32.8 g) in methanol (100 ml). The mixture was stirred and refluxed till complete dissolution. The reaction was carried out twice with the same quantities. The mixtures were combined. Ice and then ethanol were added. The mixture was allowed to crystallize out. The precipitate was filtered off, washed with ethanol and dried, yielding 58 g (86%) of 3-(3-chlorophenyl)-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-2,1-benzisoxazole (interm. 9-a).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](N)CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](N)CC4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-4-aminocyclohexyl)amide (85 mg, 0.153 mmol) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2.5 mL, 32.4 mmol) was added and the orange reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (8 mL) and ethylenediamine (1 mL, 14.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was sequentially washed with water, dichloromethane, ethyl acetate, and hexanes to afford 61 mg (93%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-4-aminocyclohexyl)-amide as a light yellow solid. MS: [M+H]+=424; 1H NMR (300 MHz, DMSO-d6) δ: 9.05 (d, J=1.0 Hz, 1H), 8.47 (d, J=9.1 Hz, 1H), 8.42 (d, J=1.0 Hz, 1H), 8.08 (d, J=7.1 Hz, 1H), 7.98 (s, 1H), 7.40 (d, J=9.1 Hz, 1H), 4.17 (d, J=1.0 Hz, 3H), 4.00 (br. s., 1H), 2.96 (br. s., 1H), 1.87-2.02 (m, 2H), 1.66-1.76 (m, 2H), 1.55-1.66 (m, 2H), 1.44-1.54 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9](=O)/[CH:10]=[CH:11]/[CH3:12]>Cl.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([CH:9]=[CH:10][C:11]([CH3:12])=[N:5]2)=[CH:7][CH:8]=1
Reactant: C/C=C/C=O
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1ccc2ccc(Cl)cc2n1

Procedure:
To a solution of m-chloroaniline (25.51 g, 0.2 mol) in 100 mL of 6N HCl kept at reflux is added dropwise with stirring 85% aqueous crotonaldehyde (14.7 g, in 2.6 g of water). After an additional 45 minutes at reflux, the mixture is cooled and extracted with ethyl ether to remove tars. To the vigorously stirred solution is added ZnCl2 (27.2 g, 0.20 mol). A tan gum ball is formed. The mixture is then refluxed for a total of three hours to give a clear brown solution. Upon cooling, a gummy solid is formed which is filtered and triturated with 2-propanol followed by ethyl ether and dried in vacuo to give the quinaldine HCl-ZnCl2 complex. The 7-chloroquinaldine is then isolated by dissolving the complex into 150 mL of water and 50 mL of NH4OH, and concentrated to yield the crude product (tan solid 15.77 g, 44.4%). Purification of the crude product is achieved by flash chromatography, (silica Merck 60, methylene chloride:ethyl acetate 98:2). Removal of the solvent affords a light tan solid (11.1 g, 31.3%), m.p. dec. 68°-70° C. (lit: 42%, m.p. 75°-77° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.O.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Yield: 79 %

Procedure:
A solution of (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11A (First Eluting Compound), 5.37 g, 11.93 mmol) in THF (160 ml), water (40 ml), and methanol (40 ml) was stirred at 50° C. overnight. The volatiles were removed under reduced pressure and the resulting residue was diluted with water (100 ml). The pH of the solution was adjusted to ˜5 with 1N aq. HCl (35 ml) promoting the formation of a precipitate. The white solid was collected via filtration and washed with water (˜150 ml). The filter cake was dried overnight under high vacuum at 50° C. to provide the title product (4.0 g, yield: 79%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[C:13]([CH3:19])=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:30]2([CH2:33][C:32](=[O:34])[CH2:31]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH2:29][C:30]2([CH2:31][C:32]([CH2:19][C:13]3[C:12]([Br:11])=[CH:17][N:16]=[C:15]([Cl:18])[CH:14]=3)([OH:34])[CH2:33]2)[CH2:35][CH2:36]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Reactant: Cc1cc(Cl)ncc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)(Cc1cc(Cl)ncc1Br)C2
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 mol/L in tetrahydrofuran; 8.0 mL) is added dropwise to 5-bromo-2-chloro-4-picoline (0.81 g) dissolved in tetrahydrofuran (10 mL) at −45° C. under Ar atmosphere. The solution is stirred at −35 to −45° C. for 0.5 h prior to dropwise addition of 2-oxo-7-aza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.00 g) dissolved in tetrahydrofuran (5 mL). The reaction mixture is stirred at −40° C. for 45 min before the cooling bath is removed. At room temperature the reaction is quenched with aqueous NH4Cl solution and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the title compound. LC (method 1): tR=1.36 min; Mass spectrum (ESI+): m/z=445 [M+H]+.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[OH:4][C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)c1cccc(OCOC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Ethyl 2-(3-(methoxymethoxy)phenyl)propanoate (4.17 g, 17.5 mmol) in CH2Cl2 (80 mL) was added trifluoroacetic acid (40 mL) at 0° C. The reaction mixture was stirred for 1 hrs at 0° C., and basified with NaHCO3 (60 g). The mixture was diluted with H2O (250 mL) slowly and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:4) as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7](O)=[CH:6]2.[Br:17]Br.[C:19]([O-:22])([O-])=O.[Cs+].[Cs+].CI>C(O)(=O)C.CC(C)=O>[Br:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH3:15])=[N:8][C:7]=1[O:22][CH3:19]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: BrBr
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc2c(C)nc(OC)c(Br)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (603 mg, 2.75 mmol) in acetic acid (27 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise bromine (0.15 mL, 2.92 mmol) and the mixture was stirred for 2 h at RT. The solid was then filtered and washed with acetic acid (20 mL), EtOAc (30 mL), Et2O (4×7 mL), CH2Cl2 (55 mL), saturated NaHCO3 (15 mL) and finally with H2O (10 mL). After drying under vacuum, a yellow solid was obtained (718 mg). This solid (500 mg, 1.68 mmol) was dissolved in acetone (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer before addition of Cs2CO3 (550 mg, 1.69 mmol). The mixture was stirred for 20 min at RT, MeI (1.0 mL, 16.06 mmol) was added and the mixture was stirred for 4.5 h at RT. After addition of SiO2 (3.0 g), the residue was filtered and washed several times with a mixture of cyclohexane:EtOAc=90:10 (until all the desired product was eluted). The filtrate was then concentrated to dryness at 40° C. under vacuum to give 4-bromo-3,6,7-trimethoxy-1-methylisoquinoline SMA 44070 as a yellow solid (139 mg, 23% yield).