Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C@H:13]1[C@@H:19]([OH:20])[C@H:18]([OH:21])[C@@H:17]([CH2:22][OH:23])[O:16][CH:14]1[OH:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:28](=[O:30])[CH3:29])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:15][CH:14]1[O:16][C@H:17]([CH2:22][O:23][C:28](=[O:30])[CH3:29])[C@@H:18]([O:21][C:14](=[O:15])[CH3:13])[C@H:19]([O:20][C:10](=[O:11])[CH3:9])[C@@H:13]1[NH:12][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(COCc1ccccc1)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](NC(=O)COCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 192.8 %

Procedure:
A solution of 31 (512 mg, 1.56 mmol) in pyridine (5 mL) was cooled to 0° C. To this solution was added acetic anhydride (2.5 mL, 27 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight and allowed to warm to rt. The resulting light yellow solution was diluted with CH2Cl2 (100 mL) and washed with 1 N HCl (3×50 mL), sat. NaHCO3 (2×50 mL), water (2×50 mL) and sat. NaCl (1×50 mL). The combined aqueous layers were back extracted with 50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:4 to 1:1 EtOAc/hexanes to afford 745 mg (96%) of a light yellow oil. IR (thin film): 3409, 2959, 2357, 1750, 1692, 1520 cm−1. 1H NMR (300 MHz, CDCl3): δ1.90 (s, 6H), 1.99 (s, 6H), 2.06 (s, 6H), 2.18 (s, 6H), 3.79-3.84 (m, 1H), 3.91-3.99 (m, 1H), 4.02 (d, 2H, J=2.8), 4.04-4.07 (m, 2H), 4.14 (dd, 2H, J=2.7, 17.8), 4.20 (dd, 1H, J=3.9, 9.1), 4.5 (app t, 1H, J=6.3), 4.60-4.65 (m, 4H), 4.66-4.68 (m, 1H), 4.79 (ddd, 1H, J=1.6, 3.8, 13.2), 5.07 (dd, 1H, J=3.9, 9.8), 5.19 (app t, 1H, J=4.7), 5.24 (app t, 1H, J=9.8), 5.35 (dd, 1H, J=4.2, 10.2), 5.90 (d, 1H, J=1.6), 6.03 (d, 1H, J=1.6), 6.89 (d, 1H, J=-9.6), 7.03 (d, 1H, J=9.3), 7.32-7.39 (m, 10H). 13C NMR (125 MHz, CDCl3): δ20.3, 20.4, 20.6, 20.7, 20.8, 48.6, 61.7, 65.1, 65.2, 68.9, 69.1, 69.3, 70.2, 71.3, 73.3, 73.5, 73.6, 77.8, 97.1, 127.8, 127.9, 128.2, 128.3, 128.4, 128.6, 128.7, 136.4, 136.6, 169.4, 169.7, 170.1, 170.5. MS (FAB) m/z 496 (MH+). Anal. Calcd for C23H29NO11: C, 55.75; H, 5.90; N, 2.83; Found: C, 55.54; H, 5.93; N, 2.68.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].[Br:14]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:14][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:13]
Reactant: COC(=O)c1cc(C)ccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: COC(=O)c1cc(CBr)ccc1OC

Procedure:
A mixture of 2-methoxy-5-methylbenzoic acid methyl ester (J.Chem.Soc.Perkin Trans.1, 1994, 1125) (1.47 g) and N-bromosuccinimide (1.45 g) in benzene (15 ml) was irradiated under a 500 W halogen lamp for 3 hours. The solvent was evaporated and the residue triturated with diethyl ether. The succinimide was filtered off and the filtrate evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([CH3:8])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of 1-Bromo-2-fluoro-4-methyl-benzene (5.35 g, 28.30 mmol) in concentrated sulfuric acid (25 ml) was added concentrated nitric acid(9 ml) dropwise while maintaining an internal reaction temperature below 20° C. The reaction mixture was stirred at 0° C. for 10 minutes and poured into ice water. The resulting mixture was extracted three times with ether. The combined ether extracts were washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 2 to 3% ethyl acetate in hexanes give 1-Bromo-2-fluoro-4-methyl-5-nitro-benzene as a white solid (5.21g, 78%).
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.OCCCCCCCCCCCCCCCC(O)=O.[CH:45]1([N:51]=[C:52]=[N:53][CH:54]2[CH2:59][CH2:58][CH2:57]CC2)CCCCC1>O1CCCC1>[CH3:1][N:51]([C:52]1[CH:57]=[CH:58][CH:59]=[CH:54][N:53]=1)[CH3:45]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)CCCCCCCCCCCCCCCO
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 365 mg of radicicol, 681 mg of 16-hydroxyhexadecanoic acid, 20 ml of dry tetrahydrofuran, 516 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 661 mg of the title compound were obtained as crystals melting at 85°-86° C.
Reaction SMILES: [CH:1]1([CH:6]=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1>>[CH:1]1([CH:6]([OH:7])[C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=CC1CCCC1
Product: CCOC(=O)c1ccc(C(O)C2CCCC2)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclopentanecarbaldehyde and ethyl 4-iodobenzoate. 1H NMR (400 MHz, CDCl3, δ): 8.01 (d, J=8.4 Hz, 2H), 7.40-7.44 (m, 2H), 4.49 (d, J=8.0 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 2.19-2.21 (m, 1H), 1.82-1.87 (m, 2 H), 1.41-1.67 (m, 6H), 1.39 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.C(O[C:10](=[NH:17])[CH2:11][C:12](OCC)=[O:13])C.[NH:18]1[C:22]([NH2:23])=[CH:21][CH:20]=[N:19]1>C(OCC)(=O)C.C(O)C>[NH2:17][C:10]1[NH:23][C:22]2[N:18]([N:19]=[CH:20][CH:21]=2)[C:12](=[O:13])[CH:11]=1
Reactant: Nc1ccn[nH]1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(=O)n2nccc2[nH]1
Temperature: 0 °C

Procedure:
Sodium bicarbonate (3.9 g, 46.2 mmol) is added in small portions to a mixture of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (Z-1) (8.6 g, 44.0 mmol) in crushed ice (100 g) and ethyl acetate (50 mL) until the pH value reaches 8-9. The organic layer is separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers are dried over anhydrous MgSO4 and filtered. The filtrate is concentrated in vacuo to afford a colourless oil which is added to a solution of 1H-pyrazol-5-amine (3.65 g, 44.0 mmol) in ethanol (100 mL). The resulting mixture is then degassed and backfilled with argon (three cycles) and stirred at reflux overnight. The mixture is then filtered while it was still warm. The solid is rinsed with cold ethanol (25 mL) and ether (2×25 mL), and then dried in vacuo to afford 5-aminopyrazolo[1,5-a]pyrimidin-7(4H)-one (Z-2).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[N:18]([CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:20][N:21]=3)[CH2:12]2)=[O:9])=[N:6][CH:7]=1.[CH3:25][C:26]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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:16]1([N:13]2[CH2:14][CH2:15][C@H:11]([NH:10][C:8]([C:5]3[N:4]=[CH:3][C:2]([CH:25]=[CH2:26])=[CH:7][N:6]=3)=[O:9])[CH2:12]2)[C:17]2[N:18]([CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:20][N:21]=1
Reactant: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(Br)cn1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Temperature: 120 °C
Yield: 46.2 %

Procedure:
To a solution of (S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.10 g, 0.26 mmol, 1 eq) in 1 mL of DMF was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.13 g, 0.84 mmol, 3.2 eq), followed by K2CO3 (0.18 g, 1.3 mmol, 5 eq) in 0.2 mL of H2O and Pd(dppf)Cl2 (0.02 g, 0.02 mmol, 0.1 eq). After heating for 1 h at 120° C. the mixture was concentrated and purified by silica gel column chromatography (EtoAc:MeOH 1:1) followed by HPLC to afford (S)—N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)-5-vinylpyrimidine-2-carboxamide (0.040 g, 0.12 mmol, 46%).
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[N:8]=[CH:9][NH:10][C:11](=[O:13])[CH:12]=1)[C:3]([F:6])([F:5])[F:4].[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:12]1[C:11](=[O:13])[NH:10][CH:9]=[N:8][C:7]=1[C:2]([F:1])([F:14])[C:3]([F:6])([F:5])[F:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(C(F)(F)C(F)(F)F)nc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cnc(C(F)(F)C(F)(F)F)c1Cl
Temperature: 25 °C

Procedure:
A solution of 4-pentafluoroethylpyrimidin-6-one (0.4 g) and N-chlorosuccinimide (0.27 g) in dry dimethylformamide (5 ml) was heated to 80° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was poured into water, and extracted into ethyl acetate. The organic layer was dried, over anhydrous magnesium sulphate, filtered, and evaporation of the solvent under reduced pressure gave a brown oil. Recrystallisation from water gave 5-chloro-4-pentafluoroethylpyrimidin-6-one
Reaction SMILES: [CH2:1]([Sn:9](I)(I)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH2:20]>>[CH2:1]([Sn:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Sn](I)(I)CCCCCCCC
Reactant: O
Product: CCCCCCCC[Sn](=O)CCCCCCCC

Procedure:
Similarly, di-n-octyltin diiodide reacts with water to produce di-n-octyltin oxide according to the reaction:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[C:4]([CH3:18])[CH:3]=1.[CH3:19][O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>O.O1CCOCC1.O.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]>[CH3:18][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=2)[C:21]([O:20][CH3:19])=[O:22])[O:6][C:5]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17]
Reactant: Cc1cc(Br)oc1C=C1C(=O)Nc2ccccc21
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2cc(C)c(C=C3C(=O)Nc4ccccc43)o2)c1

Procedure:
A solution of 3-((5-bromo-3-methylfuran-2-yl)methylene)indolin-2-one (125 mg, 0.41 mmol), 3-(methoxycarbonyl)phenylboronic acid (115 mg, 0.64 mmol), Cs2CO3 (270 mg, 0.83 mmol) and PdCl2(dppf) (16 mg, 0.02 mmol) in H2O/dioxane (5%, 5 mL) was heated at reflux for 1 h. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (100 mL) and dried over Na2SO4 and concentrated to yield the desired methyl 3-(4-methyl-5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoate. LCMS (ES): m/z 360 [M+1]+.
Reaction SMILES: S(S([O-])=O)([O-])(=O)=[O:2].[Na+].[Na+].[C:10]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=NO)[CH3:24])=[CH:18][CH:17]=1)([O:12][CH3:13])=[O:11].Cl>O.CO>[C:10]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:2])[CH3:24])=[CH:18][CH:17]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)COc1ccc(CC(C)=NO)cc1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)=O)cc1

Procedure:
Sodium metabisulphite (26 g) in water (60 ml) was added to 1-(4-carbomethoxymethoxyphenyl)propan-2-one oxime (7.5 g) in methanol (50 ml) and the mixture refluxed for 6 hours. The reaction mixture was cooled, concentrated hydrochloric acid (30 ml) added and the mixture extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water followed by sodium bicarbonate solution. The ethyl acetate layer was dried (MgSO4) and evaporated to give the title compound as an oil which crystallised on standing, (mp 63°-70°l ). τ (CDCl3) 7.91 (3H, s), 6.30 (2H, s), 6.26 (3H, s), 5.42 (2H, s), 3.17 (2H, d, J=8 Hz), 2.87 (2H, d, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=1)[CH:17]([OH:23])[C:18]([O:20]CC)=[O:19].[OH-].[K+].O.S([O-])(O)(=O)=O.[K+]>C(O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][CH:16]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=1)[CH:17]([OH:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(O)C(Sc1cc(Oc2ccccc2)ccc1N)c1ccc(OC)c(F)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(Sc2cc(Oc3ccccc3)ccc2N)C(O)C(=O)O)cc1F
Yield: 53.1 %

Procedure:
Following a procedure similar to that described in Example 1(b), 1.85 g of ethyl 3-(2-amino-5-phenoxyphenyl)thio-3-(3-fluoro-4-methoxyphenyl)-2-hydroxypropionate [prepared as described in step (a) above ] was hydrolyzed in ethanol using an aqueous solution prepared from 334 mg of 85% caustic potash. After water and ethyl acetate had been added to the reaction mixture, its pH was adjusted to a value of 3 by the addition of an aqueous solution of potassium hydrogen sulfate. The mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue Was triturated in diethyl ether, filtered and dried to give 922 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21]Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:19][O:20][CH3:21])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COCCl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCn1ncc(Cl)c(Cl)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 583.7 %

Procedure:
4,5-Dichloro-2H-pyridazin-3-one (30 g, 182 mmol), N,N-diisopropylethylamine (47.5 mL, 258 mmol) and 4-dimethylaminopyridine (2.20 g, 18.2 mmol) were dissolved in 200 mL of methylene chloride, to which was slowly added dropwise chloromethyl methyl ether (16.6 mL, 21.8 mmol) while maintaining at 0° C. The mixture was stirred for 3 h at room temperature. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution, distilled under reduced pressure, and separated-purified by column chromatography (10% methylene chloride/ethyl acetate) to give the title compound (26.6 g, Yield: 70%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH:10]=[CH2:11])=[CH:4][CH:3]=1.[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:28]2([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>CO>[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:28]2([F:34])[CH2:29][CH2:30][N:31]([CH2:11][CH2:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[O:12])[CH2:32][CH2:33]2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CC(=O)Nc1ccc(Br)cc1
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 52 h
Yield: 64 %

Procedure:
To a solution of N-(4-bromophenyl)acrylamide (340 mg, 1.50 mmol) in methanol (10 mL) was added 4-(3-benzyloxyphenyl)-4-fluoropiperidine hydrochloride (321 mg, 1.00 mmol) followed by sodium bicarbonate (840 mg, 10.0 mmol) and the resulting suspension stirred at room temperature for 52 hours. After this time the reaction was filtered and the filtrate concentrated under reduced pressure. The residue was treated with ethyl acetate (10 mL) and the resulting suspension re-filtered and concentrated under reduced pressure. The resulting solid was treated with 10% hydrogen chloride in methanol (10 mL) and the solution re-concentrated. Subsequent trituration with ethyl acetate (10 mL) afforded 3-[4-(3-benzyloxyphenyl)-4-fluoropiperidin-1-yl]-N-(4-bromophenyl)propionamide hydrochloride in 64% yield as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:6]([CH2:23][N:24]1[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:27]=3[N:26]([CH:33]3[CH2:35][CH2:34]3)[C:25]1=[O:36])=[CH:5]2.[F-].[NH4+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:6]([CH2:23][N:24]1[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:27]=3[N:26]([CH:33]3[CH2:35][CH2:34]3)[C:25]1=[O:36])=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)OCCCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)cc2cc(Br)ccc21
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: O=c1n(Cc2cc3cc(Br)ccc3n2CCCCO)c2cnccc2n1C1CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
The intermediate 11 (1.06 g, 1.14 mmol) was dissolved in methanol (30 mL), and then ammonium fluoride (0.172 g, 4.6 mmol) was added. The resulting mixture was stirred at 60° C. overnight. The reaction mixture was allowed to cool down to room temperature, then the solvent was removed. The residue was purified by column chromatography dichloromethane methanol to yield the product as a white solid (323 mg, 62%). m/z=456 (M+H)+.
Reaction SMILES: [CH2:1]1[NH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][CH2:11][C@@H:2]12.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[CH3:23][C:22]([Si:19]([CH3:21])([CH3:20])[O:8][CH2:7][C@@H:5]1[CH2:4][N:3]2[CH2:9][CH2:10][CH2:11][C@H:2]2[CH2:1][NH:6]1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CN2CCC[C@H]2CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCC[C@H]2CN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.1 %

Procedure:
To a solution of (3R,8aS)-octahydropyrrolo[1,2-a]pyrazin-3-ylmethanol (Tetrahedron Asymmetry, 1996, 7(7), 1999-2005) (531.5 mg, 3.39 mmol) in 20 mL of dichloromethane was added triethylamine (1.423 mL, 10.17 mmol) and tert-butyldimethylsilyl chloride (1.026 g, 6.78 mmol). The solution was stirred at room temperature for 2 days. The reaction was diluted with dichloromethane and extracted with sat. NaHCO3 and brine. The product was isolated by flash chromatography (dichloromethane to dichloromethane: MeOH 99:1 to 90:10), obtaining 157 mg of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C1CCN(C2CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 92.7 %

Procedure:
To a cold (0° C.) solution of 1-cyclopropyl-piperidin-4-one (1.5 g, 11 mmol, 1.0 eq.) in absolute ethanol was added sodium borohydride (306 mg, 8 mmol, 0.75 eq.). The reaction mixture was stirred at room temperature for 65 h. The mixture was concentrated in vacuo. Ice water (10 mL) was added, followed by an aqueous solution of sodium hydroxide (28% w/w, ca. 10 mL) and dichloromethane (20 mL). The mixture was stirred at room temperature for 2 h. After phase separation, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude mixture was purified on silica eluting with DCM/2N NH3 in methanol 93/7, yielding to 1.44 g (95%) of the desired product as a colorless oil. MS (m/e): 423.1 (MH+, 100%)
Reaction SMILES: [C:1]1(/[C:7](/[CH3:13])=[CH:8]/[S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCOCC1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([NH:12][S:9](/[CH:8]=[C:7](/[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)\[CH3:13])(=[O:10])=[O:11])=[O:24]
Reactant: C/C(=C\S(N)(=O)=O)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C/C(=C\S(=O)(=O)NC(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 100 °C
Reaction time: 18.5 h

Procedure:
(E)-2-Phenyl-propene-1-sulfonic acid amide is dissolved in dioxane followed by the addition of potassium carbonate and 2,4-dichlorobenzoyl chloride. The resulting solution is stirred in a sealed tube at 100° C. for 18.5 h, cooled to room temperature (RT) and partitioned between 1M HCl and ethyl acetate. The aqueous phase is separated and extracted with further portions of ethyl acetate. The organic fractions are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. After flash column chromatography (dichloromethane) (E)-2-phenyl-propene-1-sulfonic acid 2,4-dichlorobenzoylamide can be isolated as a colourless oil. Yield 90 mg (80%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:32][C:33]1[N:38]=[C:37](Cl)[CH:36]=[CH:35][N:34]=1>CN(C)C=O>[Cl:32][C:33]1[N:38]=[C:37]([N:21]2[CH:22]=[C:17]([CH:16]3[C:11]4[N:12]=[C:13]([CH3:15])[O:14][C:10]=4[CH:9]=[CH:8][C:7]4[CH:25]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]3=4)[C:18](=[O:24])[NH:19][C:20]2=[O:23])[CH:36]=[CH:35][N:34]=1
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O

Procedure:
A solution of the product from step (vii) (4.50 g), cesium carbonate (4.37 g) and 2,4-dichloropyrimidine (3.00 g) in dry N,N-dimethylformamide (30 ml) was stirred for 25 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer dried (MgSO4). Evaporation of the solvent gave an oil which was purified by column chromatography eluting with 50-100% ethyl acetate in 40-60 petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6].C(N(CC)C(C)C)(C)C.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][N:37]=1>ClCCl>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([C:4]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:2]([NH:1][C:40](=[O:41])[C:39]4[CH:43]=[CH:44][C:36]([F:35])=[N:37][CH:38]=4)[CH:3]=3)=[O:6])[CH2:8][CH2:9]2)=[CH:15][CH:16]=1)#[N:19]
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: Cc1ccc(C(=O)N2CCCC(c3ccc(C#N)cc3)CC2)cc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCCC(c3ccc(C#N)cc3)CC2)cc1NC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a 4-mL vial containing 4-(1-(3-amino-4-methylbenzoyl)azepan-4-yl)benzonitrile (compound 40.5, 44 mg, 0.13 mmol, 1.0 equiv) was added dichloromethane (1 mL) and N,N-diisopropylethylamine (35 μL, 0.20 mmol, 1.5 equiv). A solution of 6-fluoronicotinoyl chloride (22 mg, 0.14 mmol, 1.05 equiv) in dichloromethane (1 mL) was added dropwise over about 2 minutes. The resulting mixture was stirred at room temperature for 19 hours then diluted with dichloromethane (5 mL) and washed with 1 M NaH2PO4 (3 mL), saturated sodium bicarbonate (3 mL) and brine (3 mL). The organics were dried (Na2SO4), filtered and concentrated to obtain the title compound as a brown wax (64 mg, theoretical). m/z (ES+) 457 (M+H)+.