Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])[CH3:2].C([Li])(CC)C.[O:17]1[C:21]2([CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)[O:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>C1COCC1>[F:10][C:6]1[C:5]([F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[CH:24]1[CH2:25][CH2:26][C:21]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:22][CH2:23]1
Reactant: CCOc1cccc(F)c1F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC3(CC2)OCCO3)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
1-Ethoxy-2,3-difluorobenzene (s6) (102.8 g) and THF (1,000 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; in n-hexane-cyclohexane; 780 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 1,4-dioxaspiro[4.5]decan-8-one (s7) (101.5 g) in THF (500 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was mixed with p-toluenesulfonic acid (3.0 g) and toluene (500 ml). The mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (5.0 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from heptane to give 8-(2,3-difluoro-4-ethoxyphenyl)-1,4-dioxaspiro[4.5]decane (s8) (136.1 g). The yield based on the compound (s6) was 70.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:30]O.Cl>CO.CO.O.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@H:11]([C:13]3[O:20][NH:30][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
A solution of methyl 2-(4-chlorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (780 mg, 2.04 mmol) (from example 115, step 2) in MeOH (5 mL) was added to a solution of sodium hydroxide (1.705 mL, 2.05 mmol) in MeOH/H2O (1.608 mL/0.097 mL) at −30° C. After 10 min a solution of hydroxylamine hydrochloride (284 mg, 4.09 mmol) and sodium hydroxide (163 mg, 4.09 mmol) in MeOH (5 mL) and H2O (5 mL) was added. Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (3.40 mL, 20.43 mmol) at 80° C. and heated at 80° C. for 30 min. Concentration of the organic solvent and extraction with diethyl ether (×3), drying over Na2SO4 and evaporation gave a yellow foam. Purification using prepLC (pH=3, large column 20-80% MeCN over 30 min) yielded trans-methyl 2-(4-chlorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (272.5 mg, 38%). 1H NMR (400 MHz, cdcl3) δ 1.44-2.18 (m, 4H), 2.70-3.01 (m, 2H), 3.02-3.14 (m, 2H), 3.42-3.76 (m, 3H), 4.04-4.37 (m, 1H), 4.39-4.79 (m, 1H), 5.64 (s, 1H), 7.05-7.31 (m, 4H). MS m/z 351, 353 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N+:28]([O-])=[CH:27][C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1.O.[Cl-].[NH4+]>C1COCC1.CS(C)=O.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[N:28]=[CH:27][C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: COC(=O)Cc1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)[n+]([O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Reaction time: 8 h

Procedure:
Methyl (6-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]piperidin-1-yl}-1-oxidopyridin-3-yl)acetate (40 mg, 0.09 mmol) was stirred in THF (1.3 mL) at room temperature and water (1.3 mL) was added. Ammonium chloride (334 mg, 6.24 mmol) was added to the mixture followed by Zn dust (26 mg, 0.38 mmol). The reaction mixture was stirred overnight before diluting with 2 mL DMSO and filtering. The filtrate was purified by preparative HPLC to yield the title compound (Intermediate 102) as a gum; MS m/e MH+ 455.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.C(OCC)(=O)C.[H][H]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)nc1
Yield: 94 %

Procedure:
2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-(phenylsulfonyl)pyridine (Example 26, 0.52 g, 1.45 mmol) and palladium hydroxide (20% wt. Pd on carbon, 100 mg, 0.14 mmol) were stirred in acetic acid (10 mL) and ethyl acetate (5 mL) under a balloon of hydrogen for 3 hours. The catalyst was removed by filtration and the filtrate washed with 4N sodium hydroxide solution (×2). The aqueous layers were extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 2-[2-(2,4-difluorophenyl)ethyl]-5-(phenylsulfonyl)pyridine as a pale yellow solid (0.49 g, 94%). δH (500 MHz, d6 DMSO): 9.02 (1H, s), 8.23 (1H, dd, J=2.2, 8.2 Hz), 7.99 (2H, d, J=7.4 Hz), 7.70 (1H, t, J=7.4 Hz), 7.63 (2H, t, J=7.7 Hz), 7.48 (1H, d, J=8.2 Hz), 7.27 (1H, q, J=8.0 Hz), 7.11 (1H, td, J=2.0, 9.9 Hz), 6.94 (1H, td, J=1.9, 8.6 Hz), 3.07 (2H, t, J=7.7 Hz), 2.97 (2H, t, J=7.7 Hz); m/z (ES+) 360 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.ON1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[C:37]([O-])(=[O:39])C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25]([N:34]3[CH2:35][CH2:36][CH:37]([OH:39])[CH2:32][CH2:33]3)=[O:26])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: ON1CCNCC1
Reactant: CC1(C)CN(CC(=O)O)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Product: CC1(C)CN(CC(=O)N2CCC(O)CC2)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 31 %

Procedure:
The desired compound was synthesized using [5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 4-hydroxypiperazine following Method F in 31% yield. 1H-NMR (300 MHz, D2O): δ 8.85 (1H,s), 8.19 (2H, s), 7.82 (1H, s), 7.44 (1H, s), 4.15 (2H, m), 3.9-3.75 (4H, m), 3.6 (2H, m), 3.56 (2H, m), 3.12 (1H, m), 2.9 (3H, m), 2.8 (1H, m), 1.7 (2H, m) 1.34 (3H, s), 1.19 (3H, s). Retention time (LC, method: ammonium acetate standard): 1.5 min
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]=[O:19])=[CH:10][CH:9]=2)[O:4][CH2:3]1.CCOCC.[Mg+2].[Br-].[Br-].[CH2:29]([Mg]Cl)[CH:30]([CH3:32])[CH3:31]>C(OCC)C.CO.O.Cl>[CH3:1][C:2]1([CH3:20])[CH2:3][O:4][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]([OH:19])[CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:10][CH:9]=2)[O:6][CH2:7]1
Reactant: CC1(C)COC(c2ccc(C=O)c3ccccc23)OC1
Reactant: CC(C)C[Mg]Cl
Agent: Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC(C)CC(O)c1ccc(C2OCC(C)(C)CO2)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
4-(5,5-dimethyl-1,3-dioxan-2-yl)-1-naphthaldehyde (4.0 g, 14.8 mmol) was dissolved in diethyl ether (80 mL). Magnesium bromide diethyl etherate (2.8 g, 10.8 mol) was added followed by a 2M solution of isobutyl magnesium chloride in diethyl ether (8.0 mL, 16 mmol). The mixture was stirred at room temperature for 16 hours, diluted with methanol (1 mL), water (1 mL), and 1 N HCl (20 mL). The phases were separated, and the aqueous phase was extracted with ether (3×50 mL). The combined organic extracts were dried (MgSO4), and concentrated. Flash chromatography of the residue provided the 1.76 g (36%) desired product.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[S:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>CS(C)=O>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([C:5]3[S:4][N:3]=[C:2]([NH:23][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=4)[N:6]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1nsc(-c2ccc3[nH]ccc3c2)n1
Solvent: CS(C)=O
Product: COc1ccc(CNc2nsc(-c3ccc4[nH]ccc4c3)n2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
A mixture of 3-chloro-5-(1H-indol-5-yl)-1,2,4-thiadiazole (0.67 g, 2.85 mmol) and 4-methoxybenzylamine (1.95 g, 14.25 mmol, Aldrich) in DMSO (7 mL) was stirred for 12 h at 110° C. The reaction was cooled to RT and quenched with ice cold water (50 mL) and extracted into EtOAc (20 mL). The aqueous layer was back extracted with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by using silica-gel column chromatography (eluent: 30-40% EtOAc and petroleum ether) to give 5-(1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (670 mg, 70.5%) as a off brown solid. MS (ESI, pos. ion) m/z: 337.1 (M+1); 1H-NMR (300 MHz, CDCl3): δ 8.44 (brs, 1H), 8.21 (d, J=9 Hz, 1H), 7.73 (dd, J=8.4, 1.8 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.28-7.26 (m, 1H), 6.90 (dd, J=6.9, 2.1 Hz, 2H), 6.64 (m, 1H), 5.42 (m, 1H), 4.62 (d, J=7.6 Hz, 1H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7]([OH:9])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:7]([C:6]2[S:5][C:4]([CH2:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:3][C:2]=2[CH3:1])=[O:9])[CH2:57][CH2:58]1
Reactant: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)O
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)NC1CCOCC1
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (80 mg, 0.24 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (86 mg, 0.27 mmol), N,N-diisopropyl ethyl amine (210 μL, 1.21 mmol) and 4-aminotetrahydropyran (27 mg, 0.27 mmol). The resulting reaction mixture was stirred overnight and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 1:1) afforded the title compound (97 mg, 97%) as a white solid. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2]N(C(C)C)C(C)C.[SH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=2)[C:19]=1[C:39]#[N:40]>CCO.C(Cl)Cl>[CH2:1]([N:23]1[C:18]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:19]([C:39]#[N:40])[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=2)=[N:21][CH:22]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:2]
Reactant: N#Cc1c(Cl)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CS
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CSC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)=NC(c2ccccc2)N1CC
Reaction time: 2 h

Procedure:
DIPEA (8.71 ml) was added to a stirred solution of ethyl 2-mercaptoacetate (5.15 ml) and 6-chloro-5-cyano-4-(3-nitrophenyl)-2-phenyl-pyrimidine (example 31(b), 15.8 g) in a mixture of EtOH (125 ml) and DCM (125 ml)-under a nitrogen atmosphere. After 2 h at room temperature, the mixture was diluted with DCM until complete dissolution, washed with 0.5N aq. HCl, dried (MgSO4) and concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:18]>Cl.O>[ClH:18].[F:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1F
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 3-fluoro-4-methoxyaniline (1.5871 g, 11.24 mmol) in hydrochloric acid, 37% (14 ml) was diazotized with sodium nitrite (0.776 g, 11.24 mmol) in water (7 mL) and reduced with tin(ii) chloride dihydrate (1.873 mL, 22.49 mmol) in hydrochloric acid, 37% (5 ml) at 0° C. The reaction was then stirred for 20 min at room temperature. The precipitate was collected by filtration. The cake was triturated with ethanol (50 mL, room temp) followed by filtration to give a pale yellow solid as the titled compound. 1H NMR (DMSO-d6, 500 MHz) δ 10.17 (br s, 2H), 8.12 (br s, 1H), 7.10 (dd, J=9.0, 9.0 Hz, 1H), 6.96 (dd, J=13.0, 2.5 Hz, 1H), 6.80-6.76 (m, 1H) 3.76 (s, 3H), 3.42 (br s, 1H).
Reaction SMILES: Cl.CN.C1COCC1.[CH:9]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)([CH3:11])[CH3:10].[C:19]([BH3-])#[N:20].[Na+]>C(O)(=O)C.C(O)C>[CH:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH:20][CH3:19])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]
Reactant: CC(C)N1CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: CNC1CCN(C(C)C)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of methylamine hydrochloride (2.62 g, 38.8 mmol), THF (30 ml), ethanol (15 ml), N-isopropyl-4-piperidinone (3.0 ml, 20.2 mmol), and acetic acid (3.60 ml) was added sodium cyanoborohydride (30 ml, 1 molar solution in THF, 30 mmol), and the mixture was stirred at 60° C. for 6 hours and then at room temperature overnight. The mixture was concentrated under reduced pressure, water (50 ml) and potassium carbonate (47.0 g) were added, and the mixture was extracted with ethyl acetate (6×50 ml). The combined extracts were dried over magnesium sulphate and concentrated, to yield 3.78 g (quant.) of the title compound as an oil, which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH:6](O)[C:7]([OH:9])=[O:8])=[O:4].S(=O)(=O)(O)O.C(O)(=O)C.[S:20]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]1=2>O>[Cl:1][CH2:2][C:3]([NH:5][CH:6]([C:26]1[CH:27]=[CH:28][C:21]2[S:20][CH2:24][CH2:23][C:22]=2[CH:25]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: c1ccc2c(c1)CCS2
Reactant: O=C(CCl)NC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)NC(C(=O)O)c1ccc2c(c1)CCS2
Yield: 65.3 %

Procedure:
N-Chloroacetyl-α-hydroxyglycine (6.5 g., 0.038 mole) was added to a cold, stirred mixture of concentrated sulphuric acid (1.5 ml.) and glacial acetic acid (15 ml.) followed, after five minutes, by the dropwise addition of 2,3-dihydrobenzo(b)thiophen (98%, 4.1 g., 0.03 mole). The reaction mixture was stirred at ambient temperature for five hours, then water (75 ml.) was added to the resulting suspension and the mixture thoroughly stirred. Filtration gave a solid which was washed successively with water, diethyl ether and hexane, then dried, to afford DL-α-chloroacetamido-2,3-dihydro-5-benzo(b)thienylacetic acid (5.6 g.), m.p. 173°-175° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:47])[CH:10]([C:12]1[CH:46]=[CH:45][CH:44]=[CH:43][C:13]=1[CH2:14][CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)=[N:28][CH:29]=2)[N:17]=1)[CH3:11]>C(Cl)Cl>[Cl:22][C:21]1[C:16]([CH2:15][CH2:14][C:13]2[CH:43]=[CH:44][CH:45]=[CH:46][C:12]=2[CH:10]([CH3:11])[C:9]([NH2:8])=[O:47])=[N:17][C:18]([NH:23][C:24]2[CH:29]=[N:28][C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[N:19][CH:20]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
TFA (0.71 mL) was added to a solution of tert-butyl 4-(5-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-chloropyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A31 (34 mg, 0.06 mmol) in DCM (7 mL) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo before the addition of 2.0 M NaOH solution (2 mL) and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, dried over Na2SO4 and the solvent removed under reduced pressure to give the title compound 37 (23 mg, 82%). LCMS-C: rt 6.02 min; m/z 465.3 [M+H]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([CH2:12][C:13]([OH:15])=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]([CH3:26])[CH:24]=O>>[CH3:22][N:23]([CH3:26])[CH:24]=[C:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:13]=[O:15]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Phosphorus oxychloride, 690 grams (4.5 moles), is warmed to about 30° C., and 478 mL of N,N-dimethylformamide is added dropwise during a two hour period. Upon completion of addition, a solution of 202 grams (1.5 moles) of phenylacetic acid in 158 mL of N,N-dimethylformamide is added dropwise during a one hour period. Upon completion of the addition, the reaction mixture is slowly warmed to about 70°-75° C. where it is stirred for about 16 hours. After this time the reaction mixture is poured into five kilograms of ice. Two kilograms of potassium carbonate are added, and the mixture is stirred until the ice melted. The mixture is separated into two five liter reaction vessels, and 500 mL of toluene is added to each of the vessels. The stirred mixtures are then warmed to about 70° C. where they stirred for about 16 hours. After this time, the mixtures in each vessel are extracted with three 500 mL portions of toluene. The combined extracts are then washed with two one liter portions of water and one one liter portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with potassium carbonate and filtered. The filtrate is concentrated under reduced pressure, yielding 94.9 grams of crude product. The crude product is distilled under vacuum, yielding 78.3 grams of 3-dimethylamino-2-phenylpropenaldehyde, bp 154°-160° C./1 mm Hg. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-].[Na+].[Na+].[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1B(O)OOCCCCCCCC>COCCOC.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:28][C:29]1[C:34]([F:35])=[C:33]([O:25][CH2:22][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:8])[CH:32]=[CH:31][C:30]=1[C:6]1[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: CCCCCCCCOOB(O)c1cccc(F)c1F
Reactant: O=C([O-])[O-]
Reactant: OCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCOc1ccc(-c2ccccc2-c2ccc(OCCCCCCO)cc2)c(F)c1F

Procedure:
A solution of 4-bromo-4′-(6-hydroxyhexyloxy)biphenyl (3.30 g, 9.5 mmol) from step 2, a 2M-aqueous solution of sodium carbonate (40 ml) and tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.28 mmol) were mixed in DME (60 ml) under dry nitrogen at room temperature and 2,3-difluoro-octyloxyphenylboronic acid (3.25 g, 11.4 mmol) prepared as described in Example 1 step 4, was added. The stirred reaction mixture was heated under reflux under dry nitrogen overnight until g.l.c. and t.l.c. revealed a complete reaction. The product was extracted into DCM (2×150 ml) and washed with brine, water and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by column chromatography [DCM-hexane, 1:1] and recrystallised from ethanol-hexane (1:4) to give a white powder.