Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:27])[C@@H:19]([NH:23][C:24]([NH2:26])=[S:25])[CH:20]([CH3:22])[CH3:21])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:29][CH:30]=O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:27])[C@@H:19]([NH:23][C:24]3[S:25][CH:29]=[CH:30][N:26]=3)[CH:20]([CH3:21])[CH3:22])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: CC(C)[C@H](NC(N)=S)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Solvent: CCO
Product: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 1-((S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)thiourea (1.29 g, 2.86 mmol) was dissolved in EtOH (50 mL) and 2-chloroacetaldehyde (0.4 mL, 3.15 mmol) was added. The mixture was heated at 70° C. overnight. A further portion of 2-chloroacetaldehyde (0.4 mL, 3.15 mmol) was added and heating continued for a further 12 h. The solution was concentrated in vacuo and the residue was purified by column chromatography (biotage), eluting with 50% EtOAc in hexanes and then 10% MeOH in EtOAc. The desired product was isolated as a orange-brown foam (557.2 mg). LCMS (NH4OAc) shows this to be of sufficient purity. Eluting further with 100% MeOH gave a second fraction (980.8 mg) which was shown to contain the product by TLC (5:4.5:0.5 hex:EtOAc:MeOH). This second fraction from the column was re-purified to give a light orange-brown foam (426.6 mg). The two fractions were combined to afford the title compound as a orange brown foam (983.8 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].[BH4-].[Na+].Cl>C(Cl)Cl.CO>[OH:12][CH:7]1[C:6]2[C:11](=[C:2]([CH3:1])[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:5]=2)[S:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc2c(c1C)SCCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2c(c1C)SCCC2O
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
30 g (0.127 mol) of methyl 8-methylthiochroman-4-one-7-carboxylate are dissolved in a mixture of 120 ml of methylene chloride and 60 ml of methanol and the solution is cooled to 0-5° C. 2.4 g (0.064 mol) of sodium borohydride are then added a little at a time. Stirring is continued at this temperature for one hour. 200 ml of 2N hydrochloric acid are added to the reaction solution. This gives two phases. The organic phase is separated off and dried and the solvent is distilled off. The crude product is further reacted directly without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](OCC)(OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:17]#[C:18][NH2:19].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N:19][C:18]#[N:17])[CH3:1]
Reactant: N#CN
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=NC#N)c1ccccc1
Yield: 93 %

Procedure:
Following the method of Huffmann and Schaefer (J. Org. Chem. 1963, 28, 1816), a stirred mixture of 50 ml (221 mmol) triethylorthobenzoate, 9.3 g (221 mmol) cyanamide and 42 ml (442 mmol) acetic anhydride was heated at 130-150° C. for 1.5 hours with concomitant removal of the ensuing ethyl acetate and acetic anhydride by distillation from the reaction flask. The reaction mixture was then concentrated in vacuo using a rotary evaporater. Kugelrohr distillation (120° C., 3 mbar) afforded 35.8 g (93%) N-cyano-benzenecarboximidic acid ethyl ester as a colourless oil. ES-MS m/e (%): 175 (M+H+, 100).
Reaction SMILES: C(O)C.[OH-].[K+].C([O:8][C:9](=[O:30])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][CH2:18][C:17]2=[O:29])C>O>[CH2:23]([C:22]1[CH:21]=[C:20]2[C:16]([C:17](=[O:29])[CH2:18][CH2:19]2)=[CH:15][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][C:9]([OH:30])=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCc1cc2c(cc1OCCCC(=O)OCC)C(=O)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCc1cc2c(cc1OCCCC(=O)O)C(=O)CC2
Yield: 66.5 %

Procedure:
A mixture of 70 ml of ethanol, 2.7 g (0.048 mol) of potassium hydroxide, 5.9 g (0.017 mol) of ethyl4-(6-hexyl-3-oxoindan-5-yloxy)butyrate and 35 ml of water is heated for 90 minutes at the reflux point of the solvents. The solvents are evaporated off and the residue is placed in water and extracted with ether. The aqueous phase is acidified and then extracted with ether. Concentration of the solvents gives 3.6 g of product, which is purified by flash chromatography (80/20 cyclohexane/ethyl acetate): 1.5 g of crude product. Recrystallisation from hexane gives 1.3 g, m.p. 88° C., 24%.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[CH:4][C:3]=1[C:29]([CH3:32])([CH3:31])[CH3:30].[OH:33]O>>[OH:1][C:2]1[C:3]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][C:5]([S:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[O:33])=[CH:6][C:7]=1[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc(C(C)(C)C)c1O
Reactant: OO
Product: CC(C)(C)c1cc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc(C(C)(C)C)c1O

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-hydroxy-3,5di-tert. butyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH3:21][N:22](C=O)[CH3:23]>C1COCC1>[CH3:21][NH:22][CH2:23][C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: c1cc2sccc2cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNCc1cc2cnccc2s1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
A solution of thieno[3,2-c]pyridine (500 mg, 3.70 mmol) in anhydrous THF (10 mL) was stirred under argon and maintained at −78° C. while a solution of 1.6 M n-butyllithium in hexane (2.5 mL, 4.07 mmol) was added dropwise. The resulting wine red solution was stirred for 5 min. then DMF (573 μL, 7.4 mmol) was added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was treated with 10% aqueous HCl, made alkaline with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×50 mL) The combined organic fractions were concentrated in vacuo to give an oily residue which was subjected to flash chromatography on silica gel (70% ethyl acetate:hexanes) to give the title compound as a white solid (41.5%): 1H-NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.19 (d, J=5.6 Hz, 1H); MS (ES) m/e 164 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:10][CH2:11][C:12](Cl)=[O:13]>>[Cl:10][CH2:11][C:12]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[C:3]=1[CH3:9])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(N)cccc1F
Product: Cc1c(F)cccc1NC(=O)CCl

Procedure:
The subtitle compound was prepared from 3-fluoro-2-methylaniline (0.232 g) and chloroacetyl chloride (0.164 ml) by the method of Example 33 step (iii) as a beige solid. Yield: 0.3 g
Reaction SMILES: [C:1]1(C)C=CC=C[CH:2]=1.C(OCC)(=O)C.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:25]([OH:26])[CH2:1][CH3:2])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc(OC)c(OCc2ccccc2)c1
Reaction time: 0.08 h

Procedure:
To a three-neck flask, 187 ml of a 30M ethyl magnesium bromide ether solution was poured and stirred for 5 minutes under ice cooling. To this solution, 400 ml of a toluene solution in which 123.51 g of 3-benzyloxy-4-methoxybenzaldehyde was dissolved, and the mixture was added dropwise from a dropping funnel over 20 minutes. The reaction solution was stirred for additional 2 hours under ice cooling. After the completion of the reaction, the reaction solution was diluted by adding 300 ml of ethyl acetate. Further, pulverized sodium sulfate decahydrates was added to the reaction solution, which was stirred for 2 hours until a precipitate becomes smoothly. After allowed to stand still for 3 hours, the reaction solution was filtered under reduced pressure, separating into a supernatant and a precipitate. The supernatant was concentrated to dryness, affording 140.57 g of 1-(3'-benzyloxy-4'-methoxyphenyl) propanol.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH:30]([NH2:33])([CH3:32])[CH3:31]>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:6]
Reactant: CC(C)N
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a slurry of 2-amino-3-bromobenzoic acid (Aldrich; 1.00 g, 4.63 mmol) in 10 mL EtOAc in an ice bath was added 1-propanephosphonic acid cyclic anhydride (50 wt % in EtOAc; Matrix Scientific; 3.00 mL, 5.09 mmol) followed by isopropylamine (1.19 mL, 13.89 mmol). The ice bath was removed and the solution stirred rapidly at RT. A precipitate formed. After 30 min, the reaction was judged complete. The reaction was partitioned between sat'd aq. NaHCO3 and EtOAc. The organic layer was washed with sat'd aq. NaHCO3 once, sat'd NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-amino-3-bromo-N-isopropylbenzamide (1.00 g, 3.89 mmol, 84% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (2H, dd, J=7.9, 1.5 Hz), 7.25 (1H, d, J=1.4 Hz), 6.53 (2H, t, J=7.8 Hz), 5.72-6.15 (3H, m), 4.15-4.33 (1H, m), 1.27 (7H, d, J=6.7 Hz). m/z (ESI, +ve) 257.0/259.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Br:22]Br>Br.C(O)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH:8]([Br:22])[CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Br)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccc(Br)cc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 17.7 g. of 1-[3-(4-bromobenzoyl)propionyl]-L-proline (Example 36) in 150 ml. of acetic acid is added dropwise, a solution of 9.0 g. of bromine in 20 ml. of acetic acid followed by 5 drops of hydrobromic acid in acetic acid. The mixture is stirred for 18 hours, evaporated to 1/2 its volume, poured into 300 ml. of ice water and extracted with methylene chloride. The organic extract is washed twice with water, once with saturated sodium chloride solution, dried over magnesium sulfate, clarified with charcoal and evaporated to dryness in vacuo. The desired product is recovered as 20.5 g. of a white amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[CH:7]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1nnc2ccc(Br)cn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a 100 mL round-bottom flask 6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (2.124 g), 4-trifluoromethoxyphenylboronic acid (2.466 g), and sodium carbonate (0.635 g) were suspended in a mixture of DMF (81 mL) and deionized water (9 mL) that was degassed with nitrogen. Tetrakis(triphenylphosphine) palladium (0.462 g) was added and the reaction mixture stirred at 90° C. overnight, concentrated, the residue dissolved in ethyl acetate, and washed with water (2×) and concentrated NaHCO3. The combined organic phase dried over MgSO4 and concentrated, then subjected to gradient chromatography (ethyl acetate/hexane) to produce dark grey solid. The solid was recrystallized from ethyl acetate/hexanes mixture to produce off-white material.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Br)cc2)c1Br
Yield: 74 %

Procedure:
4-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 5 from 5-amino-4-bromo-3-methylisoxazole and 4-bromobenzenesulfonyl chloride in 74% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 146°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:11]([CH3:13])[CH3:12])=[C:5]([N+:14]([O-])=O)[CH:4]=1.Cl[Sn]Cl.[BH4-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:11]([CH3:13])[CH3:12])=[C:5]([CH:4]=1)[NH2:14]
Reactant: COc1ccc(C#CC(C)C)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C#CC(C)C)c(N)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-methoxy-1-(3-methylbut-1-ynyl)-2-nitrobenzene (Compound 134, 2.97 g, 13.6 mmol) in THF (45 ml) and EtOH (15 ml) at 0° C. was added SnCl2 (12.9 g, 68 mmol), followed by NaBH4 (3.1 g, 81.6 mmol) in three equal portions with one hour between each addition. The reaction was stirred at 0° C. for a total of 3.5 h and was quenched with aqueous ammonia, filtered through a pad of Celite, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][C@@H:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[C:13]4[CH:26]=[CH:27][CH:28]=[CH:29][C:12]=4[C:11]=3[N:10]=2)=[CH:4][C:3]=1[CH2:30][CH2:31][OH:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:33][S:34]([O:32][CH2:31][CH2:30][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][C@@H:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[C:13]4[CH:26]=[CH:27][CH:28]=[CH:29][C:12]=4[C:11]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[F:1])(=[O:36])=[O:35]
Reactant: OCCc1cc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)ccc1F
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCc1cc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)ccc1F

Procedure:
This was synthesized by using (R)-2-(2-fluoro-5-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)ethanol and methanesulfonyl chloride as described in general procedure 6 to afford the desired product. M.p.=99-100° C. 1H NMR 400 MHz (DMSO-d6) δ 9.58 (s, 1 H), 8.32-8.28 (m, 2 H), 7.82-7.81 (m, 1 H), 7.72-7.68 (m, 1 H), 7.51-7.42 (m, 2 H), 7.26-7.11 (m, 3 H), 7.04-7.01 (m, 2 H), 6.77 (t, 1 H), 4.64 (t, J=6.8 Hz, 1 H), 4.44-4.40 (m, 2H), 3.19-2.94 (m, 7H). LCMS m/e 508 (M+H)=508.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14]([O:16][C:17](=[O:25])[CH:18](Br)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]>CN(C=O)C>[CH2:14]([O:16][C:17](=[O:25])[CH:18]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Oc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2ccccc12)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of 25 g of 1-naphthol in 50 ml of DMF is slowly added dropwise to a solution of 7.6 g of sodium hydride dispersion in 300 ml of DMF. The suspension is stirred for 30 minutes and subsequently 41.5 g of bromomalonic acid diethyl ester in 50 ml of DMF are added dropwise. The reaction mixture is further stirred for 16 hours at room temperature and then concentrated by evaporation in a high vacuum. The residue is dissolved in ethyl acetate and washed with 2N sodium hydroxide solution, water and brine, dried over sodium sulphate and concentrated by evaporation. The residue is distilled at 145°-170°/2.6 Pa and yields α-naphthoxymalonic acid diethyl ester in the form of an orange-coloured oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:30])=[C:12]([CH3:29])[C:13]3[O:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[C:14]=3[C:27]=2[CH3:28])=O)=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:9][C:10]2[C:11]([CH3:30])=[C:12]([CH3:29])[C:13]3[O:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20]4[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=4)[C:14]=3[C:27]=2[CH3:28])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1
Solvent: CCO
Product: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 58 %

Procedure:
By using 4-methoxy-N-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 58%. Melting point: 97-98° C. (Ethanol).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:14])[CH3:13])[CH3:5].C([BH3-])#N.[Na+]>C(O)(=O)C.[OH-].[Na+].O>[CH3:1][O:2][NH:3][CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:13])[CH3:14])[CH3:5]
Reactant: CON=C(C)C1CCC(C)=CC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CONC(C)C1CCC(C)=CC1(C)C
Temperature: 24 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of 1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethanone O-methyl-oxime (135 g; 0.69 mol), prepared as described in example P5, in acetic acid (650 ml) was added portionwise sodium cyanoborohydride (67 g; 1.04 mol). The reaction mixture was stirred at 24° C. for 16 hours under nitrogen atmosphere. Most of acetic acid was removed under reduced pressure. The yellow sticky oil obtained was poured in 2M sodium hydroxide (800 ml) and water (100 ml). The solution was extracted with dichloromethane (3×300 ml). Combined organic layers were washed with sodium bicarbonate (500 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 128 g (94% of theory) of O-methyl-N-[1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethyl]-hydroxylamine (mixture of two diastereomers) as a cloudy yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[S:4][C@H:5]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]([OH:15])[C@H:6]2[N:7]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[C:17]([O:13][CH2:12][C@H:10]1[O:11][C@H:5]2[C@H:6]([N:7]=[C:3]([N:2]([CH3:16])[CH3:1])[S:4]2)[C@@H:8]([OH:15])[C@@H:9]1[OH:14])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63.8 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-2-(dimethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5 g, 20 mmol) in pyridine (150 mL) was added a solution of benzoyl chloride (3.4 g, 24 mmol) in dichloromethane (10 mL) at 0° C. within 10 minutes, and then stirred for 5 hours at 0° C. in an ice/salt bath. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (2×20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography with 2% 5% methanol in dichloromethane to afford the title compound as an off-white solid (4.5 g, 63%). (ES, m/z): [M+H]+ 353.0; 1H NMR (300 MHz, CD3OD) δ 8.07-8.01 (m, 2H), 7.99-7.40 (m, 3H), 6.43 (d, J=6.6 Hz, 1H), 4.88-4.85 (m, 1H), 4.63-4.45 (m, 1H), 4.19-4.15 (m, 1H), 3.99-3.93 (m, 2H), 3.36-3.32 (m, 1H), 3.06 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].I[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: ICCOc1ccc(/C=C\CCCOc2ccccc2)cc1
Product: COC(=O)c1ccc(OCCOc2ccc(/C=C\CCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(2-iodoethoxy)-4-[(1Z)-5-phenoxypent-1-en-1-yl]benzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Cl[C:31]1[N:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:31]4[N:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: Cc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)nn1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
A suspension of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (20 mg, 0.05 mmol), 3-chloro-6-methylpyridazine (13 mg, 0.1 mmol) and Cs2CO3 (33 mg, 0.1 mmol) in dioxane (1 mL) was stirred at 150° C. in a sealed vial. After 15 h, additional 3-chloro-6-methylpyridazine (26 mg) and Cs2CO3 (66 mg) were added. The reaction was continued for an additional 3 h. The crude reaction mixture was purified by RP-HPLC to give 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(6-methylpyridazin-3-yl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 508.2 (M+H+).