Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2O)C=CC=1>CN1CCN(C)C1=O>[O:8]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(O)cc1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: OCc1ccc(Oc2ccccc2)cc1
Yield: 7.4 %

Procedure:
A solution of iodobenzene (2.0 g, 9.7 mmol), 4-hydroxybenzyl alcohol (1.0 g, 8.1 mmol), potassium carbonate (0.67 g, 4.8 mmol), copper chloride(I) (0.016 g, 0.16 mmol) and 8-quinolinol (0.023 g, 0.16 mmol) in 1,3-dimethyl-2-imidazolidinone (5 mL) was stirred at 170° C. for 20 hours. The reaction solution was filtered, extracted with ethyl acetate, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (0.12 g, yield 7%) as an oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]([CH3:28])=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:29][CH3:30])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[CH3:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[C:27]([CH3:28])=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:29][CH3:30])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCCC(c1ccc(O)cc1)c1c(C)cc2ccccc2c1OC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(CCCCC(=O)O)c2c(C)cc3ccccc3c2OC)cc1
Yield: 86.3 %

Procedure:
Ethyl 6-(4-hydroxyphenyl)-6-(l-methoxy-3-methylnaphth-2-yl)hexanoate (30 g) was stirred with potassium carbonate (90 g), iodomethane (45 ml), and DMF (150 ml) overnight at ambient temperature. The reaction mixture was poured into cooled water and extracted with IPE. The organic layer was washed with water, dried, and evaporated. The residue was dissolved in ethanol (250 ml) and refluxed with 2.5N sodium hydroxide (250 ml) for 5 hours. Ethanol was removed and the residue was acidified with conc.HCl and extracted with ethyl acetate. The organic layer was washed with water, dried, and evaporated to give the titled compound (25 g) as crude oil.
Reaction SMILES: Cl.OC(C(F)(F)F)=O.C([O:11][C:12](=[O:27])[CH:13]([CH2:22][S:23]C(=O)C)[CH:14]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15])C>>[SH:23][CH2:22][CH:13]([CH:14]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15])[C:12]([OH:27])=[O:11]
Reactant: CCOC(=O)C(CSC(C)=O)C(C)C1CCNCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C1CCNCC1)C(CS)C(=O)O
Yield: 134.6 %

Procedure:
Conc. hydrochloric acid (4 mL) was added to 2-acetylsulfanylmethyl-3-piperidin4-yl-butyric acid ethyl ester TFA salt (0.101 g, 0.252 mmol) under argon. The reaction was heated to reflux for 5 h and then concentrated under reduced pressure to give a diastereomeric mixture of the title compound (73.7 mg) as the hydrochloride salt.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[NH2:10][C@H:11]([C:19]([NH2:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[OH:20][C:19]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:21]=1
Reactant: O=C1CCCCC1=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Oc1nc2c(nc1Cc1ccccc1)CCCC2
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A methanol (30 ml) solution of cyclohexane-1,2-dione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) with cooling below -30° C., and aqueous 12.5N-NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred at below -30° C. for 30 minutes and was further stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture, and sodium bicarbonate (15 g) was added after 10 minutes stirring, the solvent then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the product. (19.7 g, yield: 82.1%).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][NH:6][C:7]([C:9]1[N:14]=[C:13]([OH:15])[C:12]([C:16](=[O:29])[NH:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:11][N:10]=1)=[O:8])C>[OH-].[K+]>[OH:15][C:13]1[C:12]([C:16](=[O:29])[NH:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:11][N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:30])=[O:3])=[O:8])[N:14]=1
Reactant: CCOC(=O)CNC(=O)c1ncc(C(=O)NCc2cccc3ccccc23)c(O)n1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1ncc(C(=O)NCc2cccc3ccccc23)c(O)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Compound 2-20 (300 mg, 0.67 mmol) was added to a 10% KOH solution (30 mL) and stirred at 50° C. for 30 min, then cooled to room temperature, washed with DCM (30 mL×2). The aqueous phase was acidified with 5% HCl to pH 23 and filtrated and dried to afford compound 2-21 as a white solid (200 mg, 79%). 1H NMR (300 MHz, DMSO-d6): δ 3.92-3.94 (d, J=6.0 Hz, 2H), 5.0-5.01 (d, J=3.0 Hz, 2H), 7.48-7.54 (m, 4H), 7.55-7.57 (m, 3H), 8.44 (br s, 1H), 9.40 (m, 1H), 9.93 (br s, 1H), 12.80 (br s, 1H), 13.56 (br s, 1H). LC-MS: (M−H)− 379.
Reaction SMILES: OC1C=CC=CC=1C1SC=C(CC(O)=O)N=1.C([O:19][C:20](=[O:34])[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[S:25][CH:26]=1)C.[Li+].[OH-]>>[OH:33][C:32]1[C:27]([C:24]2[S:25][CH:26]=[C:22]([CH2:21][C:20]([OH:34])=[O:19])[N:23]=2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cc1csc(-c2ncccc2O)n1
Agent: O=C(O)Cc1csc(-c2ccccc2O)n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1csc(-c2ncccc2O)n1
Yield: 98.7 %

Procedure:
The procedure used for the preparation of 5a was repeated with 4c (335 mg, 1.27 mmol) and 2N LiOH (2.22 mL) to provide 5c (296 mg, 99%) as a white solid, which was recrystallized from EtOAc/hexane. mp 175.0°-176.0° C.; IR (KBr) 3450, 3300-2500 (br), 1729, 1697, 1449, 1189 cm-1 ; 1H NMR (DMSO-d6) δ3.83 (2H, s, CH2), 7.37 (1H, dd, J=8.5 and 4.4 Hz, Ar), 7.44 (1H, d, J=8.5 Hz, Ar), 7.63 (1H, s), 8.14 (1H, d, J=4.4 Hz, Ar), 11.70 (1H, s, OH), 12.54 (1H, s, CO2H); FDMS m/z 237 (M+ +1); Anal. Calcd for C10H8N2O3S: C, 50.84; H, 3.41; N, 11.86. Found: C, 50.77; H, 3.42; N, 11.74.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.[Li].Br[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]2)=[CH:14][CH:13]=1.C1(C2C=CC=CC=2)C=CC=CC=1.C1COCC1>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].O>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH2:3])=[N:17][CH:16]=2)[CH2:20][CH2:21]1)[CH3:26]
Reactant: CCN1CCN(Cc2ccc(Br)nc2)CC1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCN1CCN(Cc2ccc(N)nc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Add lithium 1,1,1,3,3,3-hexamethyl-disilazane (1055 mL) slowly to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (250 g), dicyclohexylphosphino)biphenyl (18.50 g), tris(dibenzylideneacetone)dipalladium (24.17 g) and THF (250 mL) at 50° C. Heat the mixture at 65° C. overnight. Cool to 37° C. and add water (500 mL). Remove half of the solvent under vacuum and add DCM (2.5 L). Filter over a celite pad and remove part of the solvent. Add methanol (300 mL) and methyl tert-butyl ether (MtBE, 600 mL) to the mixture and cool in an ice bath. Then, add hydrochloric acid 2 M in ethyl ether (800 mL) and a 32% aqueous solution of hydrochloric acid (100 mL). Remove the organic layer, and add an aqueous solution of sodium hydroxide 2 M (2500 mL). Extract the aqueous phase three times with DCM and remove the solvent under vacuum. Solve in 90 mL of toluene at 50° C. until complete dissolution and then add 80 mL of MtBE. Stir overnight at RT. Add additional MtBE (100 mL) for complete precipitation. Filter the solid and dry to afford 108.24 g of the title compound. MS (ES+): m/z=221 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[Li][CH3:14]>C(OCC)C>[CH3:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([CH3:14])([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: [Li]C
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Solvent: CCOCC
Product: CN1C(C)(C)CC(C)(O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a stirred solution of 1,2,2,6,6-pentamethylpiperidin-4-one (1.5 g, 8.88 mmol) in diethyl ether (25 mL) at rt was added MeLi (1.6 M, 5.5 mL, 8.88 mmol) slowly. The resulting mixture was stirred at rt for 30 min before it was quenched with sat. NH4Cl (15 mL). The mixture was then partitioned between EtOAc (35 mL) and sat. NaHCO3 (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude 1,2,2,4,6,6-hexamethylpiperidin-4-ol (1.51 g) as an oil. LC-MS (ESI) m/z 186 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH:29]([CH3:31])[CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:22][CH2:23]1
Reactant: CC(C)CI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 1-iodo-2-methylpropane.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:49]3[CH:48]=[C:47]4[CH2:50][CH2:51][CH2:52][C:53](=O)[C:46]4([CH3:55])[CH2:45][C:44]=3[CH:43]=[N:42]2)=[CH:37][CH:36]=1.CO>C1COCC1.Cl.O>[F:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]2[C:49]3[CH:48]=[C:47]4[CH2:50][CH2:51][CH2:52][CH:53]([CH:2]=[O:3])[C:46]4([CH3:55])[CH2:45][C:44]=3[CH:43]=[N:42]2)=[CH:39][CH:40]=1
Reactant: CC12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCCC2=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCCC2C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
To a cold (−30° C.) solution of (methoxymethyl)triphenylphosphonium chloride (13.85 g, 40.4 mmol) in THF (40 mL), was added KHMDS (0.5M in toluene, 70.8 mL, 35.4 mmol). The resulting red solution was stirred at 0° C. for 15 minutes before being treated with a solution of 205 (3 g, 10.1 mmol) in THF (40 mL). The mixture was stirred at room temperature for 24 hours. A solution of methanol in THF (1:1, 40 mL) and 4 N HCl (30 mL) was added to the mixture at 0° C. The resulting solution was allowed to stir at room temperature for 26 hours and was them poured into water (30 mL) and extracted with ether (4×50 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. Purification of the residue by flash chromatography on silica gel (0-50% ethyl acetate-hexanes) gave 2.2 g (70%) of 207 as a yellow solid. A small portion was further purified via bisulfite addition for characterization. 1H NMR (CDCl3) δ 1.12 (s, 3H), 1.35-1.49 (m, 1H), 1.67-1.8 (m, 1H), 1.87-2.0 (m, 2H), 2.28-2.48 (m, 3H), 2.9 (d, J=16.0 Hz, 1H), 3.1 (d, J=16.0 Hz, 1H), 6.18 (s, 1H), 7.16 (t, J=8.5 Hz, 2H), 7.42-7.48 (m, 3H), 9.90 (d, J=2.0 Hz, 1H); 13C NMR (CDCl3) 203.99, 162.64, 160.18, 147.26, 137.77, 136.35, 135.65, 135.62, 125.36, 125.32, 125.24, 116.09, 115.87, 113.36, 109.93, 60.78, 39.90, 34.55, 32.10, 24.52, 22.62, 18.96.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4].[N-:16]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1COCC1>[NH2:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccc(F)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 150.4 %

Procedure:
Cool a solution of 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone (93% pure by HPLC, 1000 g; 3.51 mol) and THF (5 L) to <5° C. in an ice bath. Add a solution of sodium azide (239 g; 3.68 mol, 1.05 eq) in water (800 mL) drop wise over one hour at <5° C. After stirring at <5° C. for one hour, separate and discard the aqueous layer. While still cold, add the organic layer slowly over 3 hours to a solution of triphenylphosphine (920.2 g, 3.51 mol, 1.0 eq), p-toluenesulfonic acid monohydrate (1335 g, 7.02 mol, 2.0 eq), and THF (5 L). Maintain the temperature at <15° C. throughout this addition and solids precipitate during the addition. Stir the reaction mixture at <20° C. for 2 hours and then filter the solid, wash with THF (3×2 L), and dry at 50° C. under vacuum to give 1167.4 g (85%, 92% corrected for starting material purity) of 2-amino-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone, 4-methylbenzenesulfonate as a white crystalline solid. HRMS (ESI) m/z (M+H) 222.0531 calculated for C9H8F4NO 222.0537
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9])[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:10]1([C:8](=[O:9])[CH:3]([NH:2][C:18]([C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=2)=[O:19])[C:4]([O:6][CH3:7])=[O:5])[CH2:12][CH2:11]1
Reactant: COC(=O)C(N)C(=O)C1CC1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1cccc(C(F)(F)F)c1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution (16 mL) of the compound (3.0 g, 16 mmol) obtained in Example 72a in N,N-dimethylformamide were added 3-trifluoromethylbenzoic acid (3.2 g, 17 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (3.6 g, 19 mmol), 1-hydroxybenzotriazole (2.9 g, 19 mmol) and triethylamine (4.3 mL, 31 mmol), and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (4.0 g, 66%) as a colorless oil.
Reaction SMILES: [Al].[Pb](Br)Br.[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:14](Cl)([Cl:17])([Cl:16])[Cl:15]>CN(C)C=O>[Cl:15][C:14]([Cl:17])([Cl:16])[CH:9]([C:8]1[CH:7]=[C:6]([OH:5])[CH:13]=[CH:12][CH:11]=1)[OH:10]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=Cc1cccc(O)c1
Agent: Br[Pb]Br
Agent: [Al]
Solvent: CN(C)C=O
Product: Oc1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 52 %

Procedure:
Aluminum (8.06 g, 0.3 mol) and lead bromide (3.7 g, 0.01 mmol) were added to a mixture of 3-hydroxy benzaldehyde (12.3 g, 0.1 mol) was mixed with 200 ml of dimethylformamide. Carbon tetrachloride (61.53 g, 0.4 mol) was slowly added thereto, the mixture was stirred at room temperature for 10 hours, and unreacted solid was filtered to remove therefrom. After sequentially adding 5% HCl, ethylacetate and water thereto, the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:4) to obtain the title compound (12.57 g, 91%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:10][CH2:11][C:12]#[N:13])([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].N>C(O)C.[Ni]>[CH2:1]([O:3][P:4]([CH2:10][CH2:11][CH2:12][NH2:13])([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: CCCCP(=O)(CCC#N)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCCCP(=O)(CCCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16.46 g of 2-cyanoethyl(n-butyl)phosphinic acid ethyl ester are dissolved in 165 ml of ethanol, the solution is mixed with 16.5 g of ammonia and 3.0 g of Raney nickel, and the mixture is hydrogenated for 2 hours at 70°-75° under an initial pressure of 100 bar. The mixture is allowed to cool to room temperature, the catalyst is filtered off, the solvent is removed and the residue is distilled, yielding 3-aminopropyl(n-butyl)phosphinic acid ethyl ester having a boiling point of 100° (10-5 bar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7].N>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][NH2:7])[CH:8]=[CH:9][N:10]=1
Reactant: COc1cc(C#N)ccn1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc(CN)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 2-methoxyisonicotinonitrile 56-1 (1.1 g, 8.2 mmol) in methanol with 7 N NH3 was added Raney-Nickel (1.0 g). The reaction was shaken under H2 at 50 psi at room temperature in Parr shaker for 12 hours. The Raney-Nickel was removed by rotary evaporation and the filtrate was taken to dryness by rotary evaporation to give crude (2-methoxypyridin-4-yl)methanamine 56-2. MS m/z 139.2 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41](CC3C=CC=CC=3)[CH2:42][CH2:43][C:44](=[O:46])[NH2:45])=[CH:33][C:32]=2[CH3:54])=[C:28]([CH:55]([CH3:57])[CH3:56])[NH:27][N:26]=1)(=[O:3])[CH3:2]>CO.[C].[Pd]>[C:44]([CH2:43][CH2:42][NH:41][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]3[O:4][C:1](=[O:3])[CH3:2])=[N:26][NH:27][C:28]=2[CH:55]([CH3:56])[CH3:57])=[C:32]([CH3:54])[CH:33]=1)(=[O:46])[NH2:45]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(CCC(N)=O)Cc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNCCC(N)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.3 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)-amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (75 mg) in methanol (3 mL) was added 10% palladium-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-[(4-{3-[2-(carbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole (66 mg). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.03 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.04 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (43 mg).
Reaction SMILES: [CH:1]([N:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]2[C:6](=[CH:7][C:8]([NH:21][CH3:22])=[CH:9][CH:10]=2)[C:5]1=[O:23])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30].O>CN(C=O)C>[CH:1]([N:4]1[C:5](=[O:23])[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N:21]([CH3:22])[C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH:7]=2)[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)=[N:13]1)([CH3:3])[CH3:2]
Reactant: CNc1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Reactant: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)N(C)c1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12 %

Procedure:
2-Isopropyl-7-methylamino-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one (0.4 g, 1.3 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.1 g, 2.6 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 5 min then methoxyacetyl chloride (0.28 g, 2.6 mmol) was added dropwise and the reaction mixture was stirred at RT for 2 hours. After this time, water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. The residue was dissolved in THF (5 ml) and heated to 60° C. in the presence of solid sodium hydroxide (100 mg) for 2 hours. After this time the mixture was concentrated under vacuum and subjected to flash column chromatography (elution: 95% EtOAc, 5% MeOH) to give N-[3-isopropyl-1-(5-methyl-1H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-phthalazin-6-yl]-2-methoxy-N-methyl-acetamide (0.06 g, 12% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br:48][C:49]1[CH:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:52]=[C:51](Br)[CH:50]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CN(C=O)C>[Br:48][C:49]1[CH:50]=[C:51]([C:14]2[C:13]3[C:17](=[CH:18][C:10]([S:7]([N:6]([CH2:5][C:4]4[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=4[O:2][CH3:1])[C:29]4[S:33][N:32]=[CH:31][N:30]=4)(=[O:9])=[O:8])=[CH:11][CH:12]=3)[N:16]([CH3:19])[CH:15]=2)[CH:52]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:54]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c3c2)c(OC)c1
Reactant: FC(F)(F)c1cc(Br)cc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(Br)cc(C(F)(F)F)c4)cn(C)c3c2)c(OC)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.200 g, 0.351 mmol), potassium phosphate (0.260 g, 1.227 mmol), and PdCl2(dppf)-CH2Cl2 (0.029 g, 0.035 mmol). DMF (0.150 mL) was added, followed by 1,3-dibromo-5-(trifluoromethyl)benzene (0.166 ml, 1.052 mmol). The vial was flushed with argon, sealed, and stirred at 85° C. for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (silica gel, gradient elution 0 to 75% EtOAc:Hexane) to afford 3-(3-bromo-5-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.081 g, 0.121 mmol, 34.6% yield) as a white solid. m/z (ESI) 668.0 (M+H)+.