Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10]O.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: COc1cccc(CO)c1I
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(Cn2ccnc2)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of (2-iodo-3-methoxyphenyl)methanol (0.350 g, 1.33 mmol), (Organic Letters, 2001, vol. 3, #21 p. 3245-3248) imidazole (0.181 g, 2.65 mmol) and triphenyl phosphine (0.382 g, 1.46 mmol) in tetrahydrofuran (5 mL) at 0° C. was added Diethyl azodicarboxylate (40% solution in toluene; 0.664 mL). The yellow solution was allowed to warm to room temperature and stirred at 60° C. overnight. After evaporating the solvent under reduced pressure, the crude was purified by column chromatography (5% EtOAc:hexanes, 20% EtOAc; Hexanes). Yield=43%. 1H NMR: 3.90 (s, 3H), 5.19 (s, 2H), 6.43 (d, 1H, J=5.70 Hz), 6.77 (d, 1H, J=6.09 Hz), 6.93 (s, 1H), 7.10 (s, 1H), 7.24 (t, 1H, J=6.03 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:23]([O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: CC(C)(CO)CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)CC(=O)OCC(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
3.7 g of 3-[4-(tert-butyloxycarbonyl)-1-piperazinyl]-2,2-dimethylpropanol and 30 mg of 4-dimethylaminopyridine were dissolved in 10 ml of methylene chloride, and diketene was added while cooling the solution with ice. After stirring the solution for 30 minutes under cooling with ice, water was added and the solution was extracted with methylene chloride. The resulting extract was concentrated under reduced pressure to give 4.7 g of an oily product (yield: 97%). The IR and NMR data of the compound thus obtained are as follows: ##STR59##
Reaction SMILES: [Na].[CH2:2]([N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH3:21][O:22][C:23]1[C:24](=[O:32])[CH2:25][C:26]([CH3:31])([CH3:30])[CH2:27][C:28]=1[CH3:29]>C(O)C>[CH2:2]([N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:29][C:28]2[CH2:27][C:26]([CH3:30])([CH3:31])[CH2:25][C:24](=[O:32])[C:23]=2[O:22][CH3:21])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: COC1=C(C)CC(C)(C)CC1=O
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Agent: [Na]
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=O)CC(C)(C)C2)c(OC)c1
Temperature: 60 °C
Yield: 61.2 %

Procedure:
In 10 ml of ethanol, 0.32 g (13.9 mmol) of sodium was dissolved. Next, 2.36 g (8.96 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 1.58 g (9.39 mmol) of 2-methoxy-3,5,5-trimethyl-2-cyclohexenone were dissolved in ethanol and added to the mixture. The mixture was stirred with heating at 60° C. for 17 hours and concentrated. The residual liquid was purified by silica gel column chromatography to give 2.27 g of a dark red oily matter (yield: 61.2%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18](I)[CH3:19]>CC(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:19]
Reactant: CC(C)I
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OC(C)C)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
1-(4-Hydroxyphenyl)ethanone (15.0 g, 110 mmol) was dissolved in acetone (125 mL). The resultant mixture was sequentially added with potassium carbonate (30.4 g, 220 mmol) and 1-methylethyl iodide (16.5 mL, 165 mmol) and then stirred at 70° C. for 8 hours. The reaction solution was filtered, washed with acetone, and concentrated in vacuo. The obtained residue was added with water and ethyl acetate, and then extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of sodium hydroxide and brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 1-[4-(1-Methylethoxy)phenyl]ethanone (18.2 g, yield 93%) was obtained as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]2[C:20]=1[C:21]1[CH2:34][NH:33][CH2:32][CH2:31][C:22]=1[NH:23]2.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C1COCC1>[C:35]([N:33]1[CH2:32][CH2:31][C:22]2[NH:23][C:24]3[C:20]([C:21]=2[CH2:34]1)=[C:19]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N:8]2[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9]2)[C:2]=1[CH3:1])[CH:27]=[CH:26][C:25]=3[C:28]([NH2:30])=[O:29])(=[O:37])[CH3:36]
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCc2[nH]c3c(C(N)=O)ccc(-c4cccc(-n5cnc6ccccc6c5=O)c4C)c3c2C1
Yield: 39 %

Procedure:
A cloudy solution of 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (20 mg, 0.044 mmol) in THF (0.5 mL) was treated with TEA (0.019 mL, 0.133 mmol) and stirred on an ice-water bath. The mixture was treated with acetic anhydride (nominally 8.40 μl, 0.089 mmol, probably more was added) and the resulting clear solution was stirred at room temperature for 1.5 h. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC. Effluent fractions containing the desired product were treated with NaHCO3 (aq) and concentrated under vacuum. The resulting aqueous suspension was filtered and the precipitate was washed with water and dried under vacuum to provide the desired product as a white solid (7.0 mg). The filter and aqueous phase were extracted three times with EtOAc, and the organic extracts were dried and concentrated to provide additional desired product as a white solid (1.5 mg) for a total of 8.5 mg (39% yield). LCMS (M+H)+ m/z 492.2, (M+Na)+514.2. 1H NMR (400 MHz, methanol-d4) δ 8.30-8.55 (2 H, m), 7.87-7.97 (1 H, m), 7.83 (1 H, t, J=7.9 Hz), 7.70 (1 H, dd, J=7.7, 1.3 Hz), 7.61-7.68 (1 H, m), 7.44-7.59 (3 H, m), 6.90-7.05 (1 H, m), 3.58-4.61 (4 H, m), 2.86-3.08 (2 H, m), 1.80-2.21 (6 H, multiple singlets).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[CH:13][CH:12]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Clc1ccc(OCCCCC#CCCCCCCCCBr)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCCCCCCCC#CCCCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
To a solution of sodium (0.58 g.; 0.025 M.) in absolute ethanol (15 ml.) was added ethyl 4-hydroxybenzoate (4.15 g; 0.025 M.) in absolute ethanol (20 ml.) and the mixture was stirred at room temperature for 15 minutes. A solution of 1-bromo-14-(4-chlorophenoxy)-tetradec-9-yne (7.00 g.; 0.0175 M.) in absolute ethanol (20 ml). was added and the mixture was boiled under reflux with stirring for 6 hours. The reaction mixture was cooled to room temperature filtered and the solvent removed under reduced pressure. Dichloromethane (100 ml.) was added to the residual oil, the solution was washed with 5% sodium hydroxide solution (2×100 ml.), saturated sodium chloride solution (1×100 ml.), dried and evaporated. The oil thus produced was purified by chromatography on silica-gel (250 g.) in dichloromethane to give 1-(4-ethoxycarbonylphenoxy)-14-(4-chlorophenoxy)-tetradec-9-yne (3.76 g.; 44%) M.P. 52°-53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[N+:11]([O-])([OH:13])=[O:12]>ClCCl.OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: N#CCc1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: N#CCc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
To a solution of 2-chloro-phenyl-acetonitrile (15.0 g, 99.0 mmol) in the dichloromethane (50 mL) and H2SO4 (40 mL) is slowly added a mixture of H2SO4 (14 mL) and HNO3 (5.5 mL) at 0° C. The reaction mixture is stirred at 0° C. for 20 minutes, warmed to room temperature for 30 minutes and then concentrated to remove organic solvent. The solution is poured into a beaker containing ice-water (400 mL) to give a crystalline precipitate, which is collected by vacuum filtration and washed with water to give the title intermediate (13.4 g, 69.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[Li+].[OH-]>CO.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To methyl 3-nitro-1-naphthoate (2.5 g, 0.011 mole) (Aldrich) in MeOH/H2O (40 ml) (1:1) was added LiOH (1.8 g, 4 equivalents). The solution was stirred overnight at room temperature. The solvent was removed under a stream of N2. The residue was dissolved in H2O and the solution acidified with concentrated HCl. The resulting precipitate was filtered, washed with H2O and dried to yield 3-nitro-1-naphthoic acid (2.18 g) as a white solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)[CH:25]=1)(=O)C.[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[C@@H:6]1([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([O:34][CH3:35])=[C:26]([CH2:36][C:37]3[S:38][C:39]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:40][CH:41]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: COc1c(Cc2ccc(Br)s2)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c2ccccc12
Reactant: OB(O)c1ccccc1
Product: COc1c(Cc2ccc(-c3ccccc3)s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12

Procedure:
1-(β-D-Glucopyranosyl)-3-(5-chloro-2-thienyl methyl)-4-methoxynaphthalene obtained in Example 250 was treated in a manner similar to Example 106-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methoxynaphthalene. APCI-Mass m/Z 636/638 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methoxynaphthalene was treated in a manner similar to Example 158-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-methoxynaphthalene. APCI-Mass m/Z 602 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-methoxynaphthalene was treated in a manner similar to Example 159-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxynaphthalene. APCI-Mass m/Z 680/682 (M+NH4). (4) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxynaphthalene and phenylboronic acid were treated in a manner similar to Example 168 to give the desired 1-(β-D-glucopyranosyl)-3-(5-phenyl-2-thienylmethyl)-4-methoxynaphthalene. APCI-Mass m/Z 510 (M+NH4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[C:27]=3[Cl:28])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3Cl)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2,3-dichloro-phenylboronic acid (62 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC=CC=2)[CH:5]=[CH:4][C:3]=1[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:18]1>CO.ClCCl.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=2[F:30])=[N:18]1
Reactant: O=C(Nc1ccn(Cc2ccc(OCc3ccccc3)cc2Cl)n1)c1c(F)cccc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccn(Cc2ccc(O)cc2Cl)n1)c1c(F)cccc1F

Procedure:
A solution of {N-[1-({2-chloro-4-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide (for a preparation see Example 30)(0.731 g, 1.61 mmol) in methanol (35 ml) was hydrogenated using the H-cube (settings: ambient, 1 bar, 1 ml/min flow rate) and 10% Pd/C CatCart 30 as the catalyst. The solvent was removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (0.331 g); LCMS: (System 4) MH+=364, tRET=2.36 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:13]C(OC(C)(C)C)=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C@@H:9]([C:10]([OH:12])=[O:11])[NH2:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccc(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
(2S)-3-(3-Bromophenyl)-2-(tert-butoxycarbonylamino)propionic acid (5.0 g, 14.5 mmol) was suspended in 4M HCl in 1,4-dioxane (75 mL) and stirred for 16 h at r.t. The white precipitate was filtered and washed with Et2O to give the title compound (3.2 g, 89%) as a white solid that required no further purification. δH (CDCl3) 8.32 (2H, s), 7.50-7.48 (2H, m), 7.34-7.29 (2H, m), 4.22 (1H, t, J 6.2 Hz), 3.13-3.11 (2H, m).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[N+:6]([C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=1[NH:15][C:16](=[O:18])[CH3:17])([O-:8])=[O:7]>[OH-].[Na+]>[N+:6]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[NH:15][C:16](=[O:18])[CH3:17])[O:19][CH2:1][CH:3]1[O:5][CH2:4]1)([O-:8])=[O:7]
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(OCC2CO2)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
150 ml of epichlorohydrin are added, at ambient temperature, to a solution of 0.376 mol (73.7 g) of 3-nitro-4-acetylaminophenol in 375 ml of 1.1N sodium hydroxide solution. The reaction medium is left to stand at ambient temperature for 48 hours, with thorough stirring, and the expected product which has precipitated is then filtered off. After drying in vacuo and recrystallisation from benzene, this product melts at 123° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])=[C:11]([F:26])[CH:10]=1)(=[O:7])=[O:6].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>C(#N)C>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:7])=[O:6])=[CH:10][C:11]=2[F:26])=[C:17]([O:24][CH3:25])[CH:18]=1)[CH3:23]
Reactant: C1COCCN1
Reactant: CCc1ccc(Oc2ccc(NS(=O)(=O)CCCCl)cc2F)c(OC)c1
Solvent: O
Solvent: CC#N
Product: CCc1ccc(Oc2ccc(NS(=O)(=O)CCCN3CCOCC3)cc2F)c(OC)c1
Temperature: 50 °C
Yield: 36.1 %

Procedure:
To a solution of 3-chloro-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]propane-1-sulfonamide (0.38 mmol; 153 mg) in dry acetonitrile (2 mL), under argon, was added morpholine (1.1 mmol; 100 μL). The reaction was heated at 50° C. overnight. After cooling to room temperature, the mixture was hydrolysed with 5 mL of water and extracted with dichloromethane (3*2 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (62 mg; 36%) was obtained after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—40/60).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>O1CCCC1>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC)cc1
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
A solution of methyl 4-hydroxyphenylacetate (25.0 g, 0.147 mol) in tetrahydrofuran (50 ml) was added dropwise to a stirred suspension of sodium hydride (4.45 g of an 80% dispersion in oil, 0.147 mol) in tetrahydrofuran (150 ml) and the mixture was stirred for 90 minutes. A solution of methyl iodide (20.9 g, 0.47 mol) in tetrahydrofuran (50 ml) was added dropwise and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate:hexane 1:9, to give methyl 4-methoxyphenylacetate (22.0 g) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>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.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccnc3)c3cc(Br)cnc32)cc1
Temperature: 60 °C

Procedure:
To a screw top reaction tube was placed 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.2 g, 2.52 mmol, prepared according to WO2011/149950), pyridin-3-ylboronic acid (371 mg, 3.02 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (177 mg, 0.25 mmol). Degassed acetonitrile (16 mL) and 1 N Na2CO3 (16 mL) was added and the reaction tube was purged with argon, sealed and heated at 60° C. for 2 h. The reaction was cooled, filtered through a Celite pad and concentrated under reduced pressure. The residue was partitioned between EtOAc/water and extracted. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a solid. Trituration of the solid with hexanes and dichloromethane gave the desired compound. LCMS-ESI+: calc'd for C19H14BrN3O2S: 428.0 (M+H+); found: 428.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])O.[Na+].O>C(O)(CC)C>[OH:1][C:2]1[CH:16]=[C:15]([O:17][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(O)cc1O
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Reaction time: 0.25 h

Procedure:
A mixture of 20 g (80 mmol) of 2,4-dihydroxy-4′-chlorobenzophenone, 21.9 g (88 mmol) of 1-bromododecane and 8.4 g (100 mmol) of sodium hydrogen carbonate is heated in 77.6 g of sec-butanol and 25.6 g of water and refluxed for 20 hours. The reaction mixture is then stirred for 15 minutes in the presence of 0.8 g of active carbon and filtered while warm. The product crystallizes upon cooling. After recrystallization from sec-butanol, 21.5 g of pale yellow crystals are obtained having a melting point of 61-63° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=O)[O:24]C4C=CC=CC=4)[CH:17]=3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:41][NH2:42]>CN1C(=O)CCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:42][CH3:41])=[O:24])[CH:17]=3)=[CH:32][CH:33]=2)=[O:9])[C:4](=[O:34])[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: CN
Solvent: CN1CCCC1=O
Product: CNC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2)ccn1
Temperature: 40 °C
Yield: 52 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridin-2-yl)carbamate (100 mg, 0.187 mmol), NMP (3 mL) and methylamine solution (25%, 0.2 mL) was heated at 40° C. overnight. The solvent was evaporated under reduced pressure at 40° C., and then diluted with water (10 mL). The precipitate was collected by filtration, and then purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=1/1/0.01) to give the title compound as a white solid (46 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C@H:13]1[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[NH:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][N:14]2[C@@H:15]([CH3:19])[CH2:16][O:17][CH2:18][C@@H:13]2[CH3:12])=[C:4]([F:11])[CH:3]=1
Reactant: C[C@H]1COC[C@H](C)N1
Reactant: O=Cc1cc(F)c(Cl)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COC[C@H](C)N1Cc1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.8 %

Procedure:
4-Chloro-2,5-difluorobenzaldehyde (0.177 g, 1.0 mmol) and (3S,5S)-3,5-dimethylmorpholine (0.167 g, 1.10 mmol) were dissolved in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.307 g, 1.45 mmol) was added and the mixture was stirred under argon atmosphere at RT for 20 h. The mixture was diluted with dichloromethane and washed with NaHCO3 (aq). The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica eluting with gradients of ammonia in methanol and dichloromethane. The fractions containing product were pooled and evaporated to give (3S,5S)-4-(4-chloro-2,5-difluorobenzyl)-3,5-dimethylmorpholine (0.118 g, 43%) as a liquid.