Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][CH2:19][CH:18]([O:21][CH3:22])[O:17][CH3:16])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CNc1ccc(OCc2ccccc2)cc1)OC
Temperature: 100 °C

Procedure:
A mixture of 4-benzyloxyaniline (10 g), bromoacetaldehyde dimethyl acetal (12.2 g), potassium carbonate (13.8 g) and dimethylformamide (150 mL) was heated at 100° C. for 5 hours. After cooling, the reaction solution was filtered and concentrated. The residue was purified by MPLC (eluent: heptane/ethyl acetate 4:1). The product with the molecular weight of 287.36 (C17H21NO3); MS (ESI): 288 ([M+H]+), was obtained in this way.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1ccc2nccn2n1
Product: c1cn2nc(N3CCNCC3)ccc2n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
An intimate mixture of 6-chloro-imidazo[1,2-b]pyridazine [6775-88-6] (4.1 g, 26.5 mmol and piperazine [110-85-0] (11.4 g, 132.8 mmol) was heated to 120° C. and stirred as a melt under N2 blanket for 2 h. The cooled reaction was partitioned between water and ethyl acetate, the extract dried (MgSO4), and evaporated to yield 5.6 g of 6-piperazin-1-yl-imidazo[1,2-b]pyridazine which, without purification, was suspended in ethyl acetate (250 mL). To this stirred mixture was added Hunig's base [7087-68-5] (9.6 mL, 55.1 mmol) and di-tert-butyl pyrocarbonate [24424-99-5] (7.2 g, 33.2 mmol). The N2 blanketed mixture was stirred overnight at ambient temperature then partitioned between brine and ethyl acetate. The phase separated extract was dried (CaSO4), evaporated, and crystallized from ethyl acetate/heptane to provide a white crystalline powder, mp. 122-123° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 3.46 (s, 8H) 7.16 (d, J=10.11 Hz, 1H) 7.50 (s, 1H) 7.81-7.94 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 28.03, 42.66, 45.42, 79.07, 110.58, 116.43, 125.91, 131.62, 135.77, 153.88, 154.71. LRMS (ESI) m/z 304.2 [(M+H)]+, calc'd for C15H21N5O2: 303.37.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([C:28]#[CH:29])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[C:37]([NH2:38])=[CH:36][CH:35]=[CH:34][N:33]=1>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.[Cu]I.C(#N)C>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([C:28]#[C:29][C:32]1[C:37]([NH2:38])=[CH:36][CH:35]=[CH:34][N:33]=1)[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccnc1Br
Reactant: C#C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C#Cc1ncccc1N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
A mixture of tert-butyl[(2S)-1-{[tert-butyl(diphenyl)silyl]oxy}but-3-yn-2-yl]carbamate (30, 144 mg, 0.340 mmol), 2-bromopyridin-3-amine (53 mg, 0.306 mmol) (or any other suitable halide or triflate ester) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) was dissolved in degassed dry TEA (1.2 mL, 8.61 mmol) and acetonitrile (0.6 ml), stirred for 5 minutes at room temperature and treated with copper(I) iodide (7 mg, 0.037 mmol). The final mixture was placed in a preheated oil bath at +52° C. and further stirred under N2 in the dark for 4.5 h, concentrated and submitted to purification through a chromatographic cartridge of silicagel (12 g) eluted with 0.5% to 12% MeOH in DCM (UV detection at 254 nm) to give title compound (157 mg, 99% yield) as a brown solid. MS: m/z=516.3 (MH+).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[C]=O.C[O:17][C:18]([C:20]1[CH:28]=[CH:27][C:23]2[CH2:24][CH2:25][O:26][C:22]=2[CH:21]=1)=[O:19].Cl>[Br-].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2].[OH-].[Na+]>[O:26]1[C:22]2[CH:21]=[C:20]([C:18]([OH:19])=[O:17])[CH:28]=[CH:27][C:23]=2[CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc2c(c1)OCC2
Agent: [Pd+2]
Agent: Cl
Agent: [Br-]
Solvent: CCCCN(CCCC)CCCC
Product: O=C(O)c1ccc2c(c1)OCC2
Temperature: 100 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
Palladium bis(triphenylphosphine) dibromide (3 g) was added to a degassed methanolic solution (30 ml) of trifluoro-methanesulfonic acid 2,3-dihydro benzofuran-6-yl ester (5 g) and tributylamine (5 ml). The mixture was charged with carbon monoxide at 40 psi in a Berghoff pressure vessel then heated at 100° C. for 72 hours. The resulting methanolic solution of 2,3-dihydro-benzofuran-6-carboxylic acid methyl ester was treated with sodium hydroxide solution (50 ml of 2M aqueous solution) and stirred at room temperature for 18 hours. The reaction mixture was acidified to pH 1 with hydrochloric acid (5M aqueous solution) and extracted with ethyl acetate (300 ml). The ethyl acetate layer was separated and the product extracted into saturated sodium bicarbonate solution (200 ml). The sodium bicarbonate solution was acidified to pH 1 with hydrochloric acid (5M aqueous solution) and the resulting precipitate dissolved in ethyl acetate. The ethyl acetate layer was separated, dried (MgSO4) and evaporated to dryness under reduced pressure to yield the title compound (0.6 g, 20%). 1H NMR (250 MHz, CD3OD) δ: 3.20 (2H, t, J=8.6 Hz), 4.54 (2H, t, J=8.6 Hz), 7.23 (1H, d, J=8 Hz), 7.25 (1H, brs), 7.49(1H, dd, J=8 and 1 Hz).
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].C(O)(=O)/C=C\C(O)=O>>[NH2:9][C@H:2]([C:1]([O-:8])=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH4+]
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 30 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
According to the same procedure of Example 1, cells of Alcaligenes faecalis ATCC 8750 was added to 2 L of an ammonium maleate substrate solution containing 400 g of maleic acid, and the substrate solution was gently stirred at 30° C. for 24 hours. After the reaction, ammonium L-aspartate was formed with a molar yield of 99.0% based on maleic acid. To the reaction solution from which the cells had been removed by centrifugation, was added 1.23 kg of 33.3 wt % maleic acid aqueous solution at 30° C. After the addition, a temperature of the solution was 38.5° C., and pH value of thereof was 3.7. L-aspartic acid crystals were separated by filtration, so as to recover 2.37 L of mother liquors. The crude crystals were 481 g (excluding water) (93.6 wt % aspartic acid, 6.0 wt % maleic acid, 250 μm average crystal size). The crystals were washed with about 300 ml of water and dried so as to obtain 448 g (excluding water) of L-aspartic acid crystals (99.1 wt % aspartic acid weight, 0.50 wt % maleic acid, 200 μm average crystal size).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.CCOC(C)=O.C1C(=O)N([Br:22])C(=O)C1.N>C(O)(=O)C>[Br:22][C:3]1[C:4]([OH:8])=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(O)c1
Agent: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccnc(O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-pyridin-2-ol V-a (25 g, 229 mmol) in glacial acetic acid (350 mL) and EtOAc (680 mL) was treated with NBS (37.4 g, 210 mmol) and stirred at room temperature for 30 min. The mixture was then taken to pH 8 with aqueous ammonia and extracted with EtOAc. The separated organics were washed with 1:1 H2O/brine then dried (MgSO4), filtered and evaporated before purification by silica column chromatography (1-4% EtOH/DCM) to afford the desired product V-b as a white solid (8.66 g). 1H NMR (300 MHz, DMSO) δ 11.90 (s, 1H), 7.32 (d, J=6.6 Hz, 1H), 6.19 (d, J=6.6 Hz, 1H), 2.25 (s, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@@H:20]([S:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@H:18]1[CH2:42]O)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C.C(OP([CH2:59][C:60]([NH2:62])=[O:61])(OCC)=O)C.[H-].[Na+]>C(Cl)Cl.O1CCCC1>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@@H:20]([S:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@H:18]1/[CH:42]=[CH:59]/[C:60]([NH2:62])=[O:61])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: CCOP(=O)(CC(N)=O)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(N)=O
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To a solution of dimethyl sulfoxide (49.9 ml, 703 mmol) in methylene chloride (1.1 l) was added oxalyl chloride (32.1 ml, 376 mmol) at -70° C., and the reaction mixture stirred for 30 minutes, treated with a pre-cooled (-70° C.) solution of (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine(115.3 g, 251 mmol) in methylene chloride (400 ml), and stirred for 30 minutes. The mixture was treated with triethylamine (174.9 ml, 1.25 mol), stirred for 30 minutes, and stirred for additional 30 minutes after removing an ice-bath. The mixture was poured into water (500 ml), the organic layer washed with lM sodium dihydrogen phosphate (500 ml) and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. A solution of the obtained residue and 2-(diethylphosphono)acetamide (63.6 g, 326 mmol) in tetrahydrofuran (1.6 l) was treated with 60% sodium hydride (11 g, 275 mmol) under ice-cooling, and the reaction mixture stirred for 30 minutes, and concentrated. The residue was dissolved in ethyl acetate (1.5 l), washed successively with water (1 l and 500 ml) and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residual solid was collected by filtration after addition of diisopropyl ether (600 ml), recrystallized from a mixture of ethyl acetate (700 ml) and hexane (700 ml) to give the title compound (79.2 g), and the mother liquor was purified by flash column chromatography on silica gel (Wakogel® C-300, 400 ml, elution with ethyl acetate) to give a second crop (combined weight 89.4 g, 71.5% total yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:24]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: c1ccc(COC2CCCNC2)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC(OCc3ccccc3)C2)ccc1Br

Procedure:
2-Bromo-5-chlorosulfonylbenzoic acid is reacted with 3-benzyloxypiperidine by the method of Example 1. Recrystallization from ether-hexane yields the product, m.p. 177°-178° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:17][NH2:18].C1COCC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[C:3]([CH:9]([NH:18][CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1
Reactant: CN
Reactant: Nc1cnc(Cl)cc1C(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(c1ccccc1)c1cc(Cl)ncc1N

Procedure:
(5-Amino-2-chloro-pyridin-4-yl)-phenyl-methanone (360 mg, 1.547 mmol), methylamine in THF (4.5 mL, 2 M, 9.00 mmol), p-toluene sulfonic acid in acetic acid (225 mg, 12%, 0.157 mmol) are stirred at room temperature in dichloromethane (15 mL). Sodium triacetoxyborohydride (1.92 g, 9.06 mmol) is added in three separate portions over 24 hours. The reaction mixture is quenched with saturated sodium carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate. The drying agent is removed by filtration. The solvent is removed in vacuo and the residue is purified by column chromatography on silica gel using a dichloromethane and methanol gradient. This provides the desired compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[OH:10].F[C:12]1[C:17](F)=[CH:16]C(B2OC(=O)CN(C)CC(=O)O2)=[C:14](O[C@H](CC=C)C)[CH:13]=1>>[Br:1][C:2]1[C:3]([O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16])=[CH:4][C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Reactant: Oc1cc(F)cc(F)c1Br
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1Br
Yield: 80 %

Procedure:
Prepared from 2-bromo-3,5-difluorophenol in 80% yield following the procedure for (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione. 1H NMR (400 MHz, CDCl3) δ 6.59-6.43 (m, 2H), 5.94-5.80 (m, 1H), 5.22-5.09 (m, 2H), 4.47-4.36 (m, 1H), 2.59-2.37 (m, 2H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH2:8]1)[CH2:3][CH2:4][C:5]#[N:6]>CO.N.[Ni]>[NH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH2:8]1
Reactant: COc1ccc2c(c1)CC(N(C)CCC#N)CC2
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc2c(c1)CC(N(C)CCCN)CC2

Procedure:
First, 2-[N-methyl-N-(2-cyano-ethyl)-amino]-7-methoxy-1,2,3,4-tetrahydronaphthalene (6.7 g, 0.0274 mol) is dissolved in methanol (80 ml) saturated with ammonia at 20° C., then Raney nickel (0.8 g) is added and the mixture is hydrogenated at 50° C. under hydrogen pressure (5 bar) for 3 hours. The catalyst is filtered off and the filtrate is evaporated by rotary evaporation. Yield: 5.4 g. Rf value: 0.25 (alumina, eluant: 95 parts by volume of methylene chloride+5 parts by volume of ethanol).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Na][Na].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1>>[C:1]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1)([OH:3])=[O:2]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=C1OCc2ccccc21
Agent: [Na][Na]
Product: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1

Procedure:
Those 6,11-dihydro-11-oxodibenz[b,e]oxepins of this invention wherein the substituent at the 2-position is 4-hydroxy-3-pyrrolin-2,5-dione-3-yl may be prepared according to the following general reaction scheme: ##STR9## wherein R2 and R3 are as previously defined, by treating an appropriately substituted R2 and/or R3 phthalide with the disodium salt of p-hydroxyphenylacetic acid at 170°-250° C. for 2-3 hours to obtain the corresponding 4-(2-carboxybenzyloxy)phenylacetic acid. The disodium salt of p-hydroxyphenylacetic acid is formed by treating the acid with aqueous sodium hydroxide and evaporating the mixture to dryness. The phthalide is then added and the reaction is carried out as described above. The carboxybenzyloxyphenylacetic acid so produced then is cyclized by stirring with trifluoroacetic anhydride in a pressure bottle at 70°-80° C. for 1-3 hours. The intermediate R2 and/or R3 substituted 6,11-dihydro-11-oxodibenzo[b,e]oxepin-2-acetic acid trifluoroacetic acid mixed anhydride then is treated with base and acidified in order to obtain the free acid. The free acid then is treated with thionyl chloride followed by ammonia to form the corresponding acetamide which is treated with diethyl oxalate in dimethylformamide in the presence of potassium t-butoxide to form the desired R2 and/or R3 substituted 2-(4-hydroxy-Δ3 -pyrrolin-2,5-dione-3-yl)-6,11-dihydro-11-oxodibenz[b,e]oxepin of formula VI.
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.Br[Si](C)(C)C>ClCCl>[OH:5][P:4]([CH2:16][C:17]([N:19]1[C@H:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1Cc2ccccc2C[C@H]1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1Cc2ccccc2CN1C(=O)CP(=O)(O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (S)-1,2,3,4-tetrahydro-2-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-3-isoquinolinecarboxylic acid, phenylmethyl ester (1.07 g., 2.0 mmole) from Example 1(e) in dry dichloromethane (5 ml.) is treated with bromotrimethylsilane (0.4 ml., 3 mmole) and stirred at room temperature under argon for 16 hours. The mixture is evaporated to dryness and the residue is partitioned between ethyl acetate-water. The ethyl acetate phase is washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated to give (S)-1,2,3,4-tetrahydro-2-[[hydroxy(4-phenylbutyl)phosphinyl]-acetyl]-3-isoquinolinecarboxylic acid, phenylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1.[CH3:30][N:31]([CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1.NC1C=C(O)C(C)=CC=1.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(Cl)=O)=NC=NC=2N=1)(C)C>CO>[CH3:30][N:31]([CH3:39])[C:32]1[CH:33]=[C:34]([NH:38][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([S:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:11]([NH:19][C:20]3[C:21]4[CH:29]=[CH:28][CH:27]=[N:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH:12]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3ncccc23)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(N(C)C)c3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 260B was reacted with N,N-dimethyl-1,3-phenylenediamine according to the procedure from Example 137C substituting N,N-dimethyl-1,3-phenylenediamine for 5-amino-o-cresol and substituting the product from Example 260B for the product from Example 137B to provide the title compound as an off white solid after trituration of the reaction product from methanol (45 mg, 52%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.33 (s, 1 H), 9.99 (s, 1 H), 9.11 (dd, J=4.41, 1.84 Hz, 1 H), 8.96 (dd, J=8.46, 1.84 Hz, 1 H), 8.63 (s, 1 H), 8.01 (d, J=1.84 Hz, 1 H), 7.82 (dd, J=8.46, 1.84 Hz, 1 H), 7.70 (dd, J=8.09, 4.41 Hz, 1 H), 7.36-7.43 (m, 2 H), 7.10-7.20 (m, 3 H), 6.97-7.04 (m, 3 H), 6.48 (td, J=4.50, 2.39 Hz, 1 H), 3.77 (s, 3 H), 2.88 (s, 6 H); MS (ESI+) m/z 523.5 (M+H)−, (ESI−) m/z 521.2 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH-:10].[Na+].O>CN1C(=O)CCC1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:10][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: BrCc1ccc(I)cc1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Ic1ccc(COCc2ccc(I)cc2)cc1
Reaction time: 0.17 h

Procedure:
825 mg of PVA 13 kDa was dissolved in 55 ml of dry NMP under a nitrogen flow at 130° C. Then the temperature was decreased to 50° C. and 5 g of 4-monoiodobenzyl bromide was added. After 10 minutes, 1.35 g of dried sodium hydroxide was added. After 5 hours of reaction time, cold water was added and a paste material has appeared. The sticky paste could not be filtrated. Water was easily removed because the material was struck to the walls of the flask. After water was poured out, the pasty residue was washed with methanol and dried. After conventional steps of purification, MIB-PVA 13 kDa including residual NMP was obtained.
Reaction SMILES: Cl[C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[C:16]3[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH3:23])[C:11]=3[N:10]=[CH:9][C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[CH:4][CH:3]=1>CO.CC(=O)OCC.O.[Pd]>[CH2:6]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH3:23])[C:11]=2[N:10]=[CH:9][C:8]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[C:5]1[CH:31]=[CH:32][CH:2]=[CH:3][CH:4]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(F)c3)cnc21
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccccc3)c(-c3cccc(F)c3)cnc21
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a solution of 5-(4-chlorobenzyl)-6-(3-fluorophenyl)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (25 mg, 0.06 mmol) in MeOH (1 mL) was added 10% Pd/C (10 mg). The reaction was hydrogenated (15 psi) at 70° C. for 1 h, cooled to RT then diluted with EA (30 mL) and water (30 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-benzyl-6-(3-fluorophenyl)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 43.5% yield) as a solid. 1H NMR (CDCl3) δ: 8.52 (s, 1H), 7.35 (d, J=8.0, 6.0 Hz, 1H), 7.23-7.06 (m, 4H), 6.98 (t, J=8.0 Hz, 1H), 6.93-6.87 (m, 1H), 6.84 (d, J=6.9 Hz, 2H), 4.68 (s, 2H), 4.17 (dd, J=20.0, 13.9 Hz, 2H), 3.77 (s, 3H), 3.42 (t, J=5.2 Hz, 2H), 2.89 (s, 1H), 1.91-1.80 (m, 2H). LCMS: MH+ 420 and TR=2.83 min.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:4][C:3]=2[O:2]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>C1COCC1.CCOCC>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)=[O:14])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 3-(3,4-methylenedioxyphenyl)-propionic acid (501 mg, 2.58 mmol) in anhydrous THF (10 mL) were added N-methylmorpholine (0.28 mL, 2.58 mmol) and isobutylchloroformate (0.33 mL, 2.58 mmol) at 0° C. After 30 min, at 0° C., a solution of methyl 4-aminobenzoate (390 mg, 2.58 mmol) in anhydrous THF (2 mL) was added to the reaction mixture. After 30 min the temperature was allowed to warm up to rt and stir for 24 hrs. After extraction with EtOAc (100 mL), washing with HCl (0.1N, 50 mL) and a saturated aqueous solution of NaHCO3 (50 mL), the organic layer was dryed over sodium sulfate and evaporated under vacuo to give a solid. The residue was taken up in Et2O, filtrated and washed with Et2O gave the title compound as a white solid (62%) in 99.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).