Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:23][CH3:24])=[N:4][C:5]([N:9]2[CH2:16][CH:15]3[C:11]([C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]=4)([NH:12][O:13][CH2:14]3)[CH2:10]2)=[N:6][C:7]=1[CH3:8].CO>C(O)C.[Ni].O>[NH2:12][C:11]1([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:10][N:9]([C:5]2[N:4]=[C:3]([O:23][CH3:24])[C:2]([F:1])=[C:7]([CH3:8])[N:6]=2)[CH2:16][CH:15]1[CH2:14][OH:13]
Reactant: COc1nc(N2CC3CONC3(c3cnccn3)C2)nc(C)c1F
Agent: [Ni]
Solvent: CO
Solvent: CCO
Solvent: O
Product: COc1nc(N2CC(CO)C(N)(c3cnccn3)C2)nc(C)c1F
Yield: 99.3 %

Procedure:
A solution of 5-(5-fluoro-4-methoxy-6-methyl-pyrimidin-2-yl)-6a-pyrazin-2-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (0.92 g, 2.77 mmol) in ethanol (40 mL) is hydrogenated at 50 psi in the presence of Raney nickel (as a slurry in water) (2.7 g, 45.54 mmol) for 5 hours using a PARR hydrogenator. Methanol is added and the catalyst removed by filtration through a pad of diatomaceous earth. The diatomaceous earth pad is washed with methanol. The combined filtrates are concentrated under reduced pressure to give the title compound (0.92 g, 99%). ES/MS (m/e): 335 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2N.N([O-])=O.[Na+].C1CCCCC1.C(OCC)(=O)C.[F:31][B-](F)(F)F.[H+]>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2[F:31]
Reactant: COc1cc(N)c2ncc(Br)cc2c1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCCCC1
Product: COc1cc(F)c2ncc(Br)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-6-methoxy-quinolin-8-ylamine (preparation described in Journal of Pharmaceutical Sciences (1984), 73(12), 1854-6) (5.0 g) in 20 ml fluoroboric acid, (50 wt % solution in water) at ˜5° C. was treated with a solution of sodium nitrite (1.9 g in 3 ml of water) over a period of 40 minutes. The reaction mixture was stirred at room temperature for 2 hours after which time the precipitate was filtered and washed with cold diethyl ether. The resulting brown powder was added portionwise to hot dichlorobenzene over 1.5 hours. Stirring was then continued for an additional 30 min at 190° C. On cooling to room temperature, the mixture was treated with dilute hydrochloric acid and diluted with ethyl acetate. The organic phase was washed with dilute sodium hydroxide, dried over sodium sulphate, filtered and evaporated under reduced pressure to give a black oil that was fractionated by chromatography (silica; cyclohexane/ethyl acetate) to give the required product (M+256)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a mixture of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 0.307 mmol), 4-fluorophenylboronic acid (64 mg, 0.457 mmol) and Pd(Ph3P)2Cl2 (22 mg, 0.031 mmol) in dioxane (3 mL), aq. Na2CO3 (100 mg, 0.943 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 1 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, which was eluted with 5-15% EtOAc in hexane to give 2-chloro-N-cyclopropyl-5-(4-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (121 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:24](#[N:26])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([C:24]#[N:26])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)NN1CC[C@H](OS(C)(=O)=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Product: CC(C)(C)OC(=O)NN1CC[C@H](C#N)C1
Temperature: 65 °C

Procedure:
(S)-1-(tert-Butoxycarbonylamino)-3-methanesulfonyloxypyrrolidine (39 g, 0.15 mol) was dissolved in acetonitrile (250 mL) and tetra-n-butylammonium cyanide (75 g, 0.28 mol, 1.9 equiv.) was added. The resulting mixture was heated at 65° C. for 6 h and then cooled to room temperature. Saturated NaHCO3 (500 mL) was added and the reaction mixture extracted with toluene (750 mL and 300 mL). The combined organic layers were washed with water and concentrated under reduced pressure to give a brown oil. This crude material was purified by flash chromatography with 20% ethyl acetate in hexane to give (S)-1-(tert-butoxycarbonylamino)-3-cyanopyrrolidine as a yellow oil (13.5 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([NH:20][C@H:21]([C:25](O)=O)[C@@H:22]([CH3:24])[OH:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCOCC1.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:25]([C@@H:21]([NH:20][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C@H:22]([OH:23])[CH3:24])=[N:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-tert-butyl-1,2-diaminobenzene (375 mg, 2.28 mmol) in dioxane (4 mL) was added a solution of N-Boc-L-threonine (500 mg, 2.28 mmol) in dioxane (4 mL) followed by triethylamine (636 μL, 456 mmol) and T3P (1520 mg, 2.40 mmol). The reaction was stirred at room temperature for 10 minutes followed by heating to 100° C. for 18 hours. The reaction was cooled and diluted with EtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (40 mL). The organic layer was collected, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 15-100% TBME in heptanes to afford tert-butyl [(1R,2R)-1-(5-tert-butyl-1H-benzimidazol-2-yl)-2-hydroxypropyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([O:20][CH3:21])[N:13]=1)[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25].Cl.Cl.[NH2:30][CH:31]1[CH2:34][NH:33][CH2:32]1.CN1CCCC1>C(#N)C>[NH2:30][CH:31]1[CH2:34][N:33]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]3[C:12]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([O:20][CH3:21])[N:13]=3)=[CH:5][C:4]=2[F:26])[CH2:32]1
Reactant: NC1CNC1
Reactant: COc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CC#N
Product: COc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Yield: 33.1 %

Procedure:
To 500 mg of acetonitrile were added 75 mg of 8-chloro-1-(3,5-difluoro-6-methoxypyridine-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 65 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was heated under reflux for 1 hour. The precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 28 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([N:22]2[CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH2:27]2)[CH2:20][NH:21][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=2[Cl:1])=[CH:17][CH:18]=1
Reactant: NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][NH:17][C:16](=[O:19])[N:15]1[CH3:20])=[O:13].Cl.[CH3:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH2:28]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][N:17]([CH2:28][C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH3:22])[C:16](=[O:19])[N:15]1[CH3:20])=[O:13]
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(F)c1Cl
Reactant: Cc1nc[nH]c1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1nc[nH]c1CN1CC(C(=O)NCc2ccc(F)c(F)c2Cl)N(C)C1=O
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A solution of N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (152 mg, 0.5 mmol) (prepared as described in Example 28), (4-methyl-1H-imidazol-5-yl)methanol hydrochloride (93 mg, 0.625 mmol) and p-toluene sulfonic acid monohydrate (19 mg, 0.100 mmol) in N-methyl-2-pyrrolidone (1 ml) was heated at 130° C. under argon for 3 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The solution was washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC, followed by trituration with ether to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-2-oxo-4-imidazolidinecarboxamide (147 mg, 74%). LC/MS [M+H]+=398, retention time=1.57 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].[CH3:11][O-:12].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:11](=[O:12])[C:10]3[CH2:9][CH2:8][CH2:4][CH2:3][C:2]=3[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: C[O-]
Reactant: N=C(N)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(-c2cccc(Cl)c2)nc2c1CCCC2
Temperature: 85 °C
Yield: 52.2 %

Procedure:
A solution of 3-chlorobenzimidamide (5 g, 32.34 mmol) in ethanol (90 mL) was treated with ethyl-2-cyclohexaneonecarboxylate (6.3 g, 40.43 mmol) and sodium methoxide (2.1 g, 38.81 mmol). The reaction mixture was heated at 85° C. for 18 h. After this time, the reaction mixture was cooled and concentrated to a volume of approximately 50 mL. Then, 2.0 M HCl (68 mL) was added slowly. The resulting precipitate was filtered, washed with water and ether, and the residue was dried on a high vacuum overnight to afford the title compound (2.2 g, crude) as a light yellow solid. MW=260.72. 1H NMR (DMSO-d6, 300 MHz) δ 12.64 (s, 1H), 8.16-8.10 (m, 1H), 8.08-7.99 (m, 1H), 7.66-7.57 (m, 1H), 7.54 (t, J=7.9 Hz, 1H), 2.66-2.55 (m, 2H), 2.44-2.33 (m, 2H), 1.84-1.61 (m, 4H); APCI MS m/z 261 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (2000.00 mg; 10.68 mmol; 1.00 eq.) in DCM 10 ml added ethyl-diisopropyl-amine (2.49 ml; 13.89 mmol; 1.30 eq.), then added dropwise methanesulfonyl chloride (0.89 ml; 11.22 mmol; 1.05 eq.) at 0° C., the reaction mixture was stirred for overnight at RT. TLC (EA/HEX=7:3) showed staring material converted to desired completed. Diluted the reaction solution with EA, washed with brine, organic layer was dried, filtered through silica gel 10 g, most color material was absorbed on silica gel, the filtrate was evaporated off solvent, got residue as title compound directly using for the next step reaction, TLC was clean.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:5]1[CH:4]=[C:3]([CH2:2][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(CBr)cc1F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cccc(F)c2)cc1F
Temperature: 130 °C
Yield: 51.7 %

Procedure:
Methyl 4-(bromomethyl)-2-fluorobenzoate (0.300 g; 1.21 mmol) was suspended in a mixture of water (1 mL) and 1,2-dimethoxyethane (3 mL) and 3-fluorophenylboronic acid (0.193 g; 1.34 mmol), tetrakis(triphenylphosphine)palladium(0) (0.071 g; 0.0061 mmol) and sodium carbonate (0.259 g; 2.43 mmol) were successively added. The resulting suspension was heated at 130° C. in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 1 to 12% of ethyl acetate in heptane) to give 0.164 g (52%) of methyl 2-fluoro-4-(3-fluorobenzyl)benzoate as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.[CH3:21][O:22][CH2:23][CH2:24][C:25](O)=[O:26].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:19]([C:16]1[N:17]=[CH:18][C:13]([NH:12][C:8]2[N:9]=[CH:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:25](=[O:26])[CH2:24][CH2:23][O:22][CH3:21])=[N:14][CH:15]=1)#[N:20]
Reactant: COCCC(=O)O
Reactant: N#Cc1cnc(Nc2cc3cccc(N)c3cn2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC(=O)Nc1cccc2cc(Nc3cnc(C#N)cn3)ncc12
Temperature: 40 °C
Reaction time: 48 h
Yield: 11.4 %

Procedure:
To a solution of 5-(8-aminoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (36 mg, 0.14 mmol), 3-methoxypropionic acid (34 mg, 0.32 mmol), N-hydroxybenzotriazole hydrate (64 mg, 0.42 mmol) and diisopropylethylamine (78 mg, 0.60 mmol) in DMF (1 mL), was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.42 mmol). The reaction mixture was stirred at 40° C. for 48 hours and then concentrated to dryness. Preparative HPLC gave the title compound (5.7 mg, 0.016 mmol, 12%). 1H NMR (d6-DMSO, 400 MHz) δ 11.05 (br s, 1H), 10.20 (s, 1H), 9.32 (s, 1H), 8.82 (d, 1H, J=1.2 Hz), 8.71 (d, 1H, J=1.2 Hz), 8.49 (s, 1H), 7.65-7.75 (m, 3H), 3.71 (t, 2H, J=6.1 Hz), 3.32 (s, 3H, obscured by water signal), 2.75 (t, 2H, J=6.1 Hz). LC-MS (2) Rt=2.10 min; m/z (ESI+) 349 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH3:15].CC[O-].[Na+]>CCO>[CH2:14]([O:16][C:17](=[O:23])[C:18](=[O:19])[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:15]
Reactant: COc1ccc(CCC(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-methoxyphenyl)-2-butanone (14.9908 g, 84.2 mmol) and diethyloxalate (12.3434 g, 84.2 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 28.1 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred. After 10 min, the reaction completely solidified. An additional 100 mL EtOH was added, the reaction was placed on mechanical shaker overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 22. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 22. 1H (CDCl3, 400 MHz): δ 14.39 (1H, broad s), 7.10 (2H, d, J=7.1 Hz), 6.82 (2H, d, J=6.3 Hz), 6.34 (1H, s), 4.33 (2H, q, J=7.1 Hz), 3.77 (3H, s), 2.91 (2H, t, J=7.3 Hz), 2.78 (2H, t, J=7.3 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 202.53, 166.46, 162.29, 158.36, 132.36, 129.44, 114.20, 102.11, 62.75, 55.47, 43.02, 29.94, 14.27 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 55.47, 14.27; CH2 carbons: 62.75, 43.02, 29.94; CH carbons: 129.44, 114.20, 102.11 ppm. HPLC: 10.12 min. (Starting material: HPLC: 9.10 min.)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[NH:5][C:6](=O)[C:7]=1[N+:8]([O-:10])=[O:9].O(Cl)[Cl:19].P(Cl)(Cl)(Cl)=O>C(N(CC)C1C=CC=CC=1)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:19])[N:5]=[C:4]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:3]=1
Reactant: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: ClOCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(C)C(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Yield: 72 %

Procedure:
The title compound of Example 23 (10.0 g, 38.37 mmol) was heated to reflux in phosphorus oxychloride oxychloride (200 ml) and N,N-diethylaniline (3-4 drops) for 5 hours under nitrogen. The solution was then cooled to room temperature, concentrated to dryness, and the syrup was dissolved in cold (~-10° C.) methylene chloride (200 ml). The organic layer was treated with saturated aqueous sodium bicarbonate (100 ml) with vigorous stirring, and the temperature was kept below 5° C. as solid sodium bicarbonate was added portionwise to elevate the pH to between 5 and 7. The layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic layers were filtered over phase-separator paper, concentrated and dried under vacuum to give the title compound (7.71 g, 72%) as a yellow-white solid sufficiently pure to employ in the next step. Recrystallisation of the solid from hexane/methylene chloride provided an analytical sample, m.p. 166°-169° C.; 1H-NMR (DMSO-d6) δ 1.09 (d, J=6.9 Hz, 6H, (CH3)2CH), 2.79 (m, J=6.9 Hz, 1H, (CH3)2CH), 11.61 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:23])=[CH:13]/[C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:40][C:41]1[NH:45][N:44]=[N:43][N:42]=1>C(Cl)(Cl)Cl.CN(C)C=O.CN(C)C=O.C(Cl)(Cl)Cl>[NH:42]1[C:41]([NH:40][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14](/[CH:13]=[C:12](/[C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[O:5][CH2:4][CH2:3][C:2]4([CH3:1])[CH3:24])\[CH3:23])=[CH:22][CH:21]=2)=[N:45][N:44]=[N:43]1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Reactant: Nc1nnn[nH]1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C/C(=C\c1ccc(C(=O)Nc2nnn[nH]2)cc1)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 0.5 g (1.55 mmole) of 4-[(E)-2-(4,4-dimethyl-6-chromanyl)-2-methylvinyl]benzoic acid in 20 ml of chloroform-N,N-dimethylformamide (1:1) at -25° C., under nitrogen, was added 0.17 g of triethylamine followed by 0.23 g (1.7 mmole) of isobutyl chloroformate. Stirring was continued for 15 minutes at -25° C. and then a solution of 0.177 g (1.7 mmole) of 5-aminotetrazole in 4 ml of N,N-dimethylformamide was added dropwise during 2 minutes. Stirring was continued for 1 hour as the reaction mixture was allowed to warm to 25° C. The reaction mixture was then diluted with 50 ml of chloroform and washed with 50 ml of 1N hydrochloric acid. The insoluble material was recovered by filtration to give a first crop of the title compound. The layers were then separated and the chloroform layer was washed with 1N hydrochloric acid followed by saturated sodium chloride, dried (MgSO4) and concentrated in vacuo. The residue was triturated under hot chloroform and the insoluble material was collected by filtration to give a second crop of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N:5][CH:4]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[C:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[N:5][CH:4]=[C:3]2[CH2:2][N:39]1[CH2:40][CH2:41][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])[CH2:37][CH2:38]1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cc2ncc(CN3CCN(c4ccccc4OC)CC3)c3cc(OC)c(OC)cc23)cc1OC
Yield: 79.2 %

Procedure:
A mixture of 10.0 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline, 5.5 g of 1-(2-methoxyphenyl)piperazine, and 7.6 ml of triethylamine in 100 ml of dimethylsulfoxide was heated at 80° for one hour under argon. The cooled solution was then diluted with water and extracted with methylene chloride. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate, charcoaled, and evaporated. The residue was crystallized from ethanol to give 11.1 g of 6,7-dimethoxy-1-{(3,4-dimethoxyphenyl)methyl}-4-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]isoquinoline as a yellow solid, mp 117°-119°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH:8](=[O:12])[CH2:9][CH2:10][CH3:11].[ClH:13]>C[Si](C)(C)N[Si](C)(C)C.O>[ClH:13].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: CCCC=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CCCC(O)P(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.46 of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours. The resulting clear solution is cooled to room temperature and 14.8 g of freshly distilled n-butyraldehyde are added. An exothermic reaction ensues, the reaction temperature, rising to approximately 60° C. The reaction mixture is stirred for 1 hour at a temperature between 10° and 60°. After cooling to room temperature, the volatile materials are removed in vacuo to yield a colourless oil. This oil is dissolved in water and stirred at room temperature for 1 hour and the aqueous layer is evaporated to dryness at 55°. A semi-solid residue is obtained which is dissolved in 50 ml of 2.0M aqueous hydrochloric acid and washed with dichloromethane, (3×100 ml), and ether (1×100 ml). After removal of the water the white solid is co-evaporated with water (10×50 ml), and then with 10×50 ml of absolute ethanol. Crystallisation of the residue form ethanol yields 3-aminopropyl(1-hydroxybutyl)phosphinic acid hydrochloride, m.p. 154°-160°. Treatment of the hydrochloride with propylene oxide/ethanol or passage through a DOWEX® 50 W×8 (14-40 mesh) ion-exchange column gives 3-aminopropyl(1-hydroxybutyl)phosphinic acid, m.p. 187°-188°, as a white solid.