Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([O:37]CC2C=CC(OC)=CC=2)=[O:36])=[CH:4]1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)OCc2ccc(OC)cc2)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a suspension of 4-methoxybenzyl 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (68 g, 108 mmol) in a mixture of Methanol (250 mL) and Water (125 mL) was added KOH (12.16 g, 217 mmol) portionwise. The resulting mixture was stirred at 90° C. for 3 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to r.t. and concentrated, and was then diluted with water and adjusted pH to 1 using 6 N HCl (aq.). The precipitates were collected by filtration and dried to afford 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 g, 99 mmol, 91% yield) as a brown solid. LCMS: (M+H)+: 508.2.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]1[O:30][C@@H:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:16][CH:17]=1)[CH2:22][C@H:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1ccc(OCCNCc2ccccc2)cc1
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: CC(C)O
Product: NC(=O)Cc1ccc(OCCN(Cc2ccccc2)C[C@H](O)c2ccccc2)cc1
Yield: 64.8 %

Procedure:
A mixture of 4-[2-(benzylamino)ethoxy]phenylacetamide (OLS 2135678) (14.0 g), (R)-styrene oxide (5.92 g) and propan-2-ol (200 ml) was heated under reflux for 72 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was purified by dry, flash column chromatography. Elution with 10% methanol in dichloromethane gave (R)-4-[2-(N-benzyl-N-(2-hydroxy-2-phenylethyl)amino)ethoxy]phenylacetamide as an oil (12.9 g). This reaction may also be performed in t-amyl alcohol under reflux.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].BrCC1OC(C(F)(F)F)=CC=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:25]1=[O:45].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[O:45]=[C:25]1[C:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using methyl 3-bromomethylbenzoate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, methyl 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (99%) as a colorless solid: mp 89-97° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.98-7.95 (m, 2H), 7.51-7.42 (m, 2H), 7.19-7.14 (m, 2H), 7.03-7.01 (m, 1H), 6.73-6.70 (m, 1H), 6.50 (s, 1H), 6.27 (s, 1H), 5.19-5.13 (m, 1H), 4.95-4.92 (m, 1H), 4.84-4.79 (m, 1H), 4.67-4.64 (m, 1H), 4.19-4.11 (m, 4H), 3.90 (s, 3H) 13C NMR (75 MHz, CDCl3) δ 177.6, 166.7, 153.3, 144.7, 141.7, 138.4, 136.1, 132.3, 131.7, 130.8, 129.2, 128.9, 128.1, 124.0, 123.6, 120.9, 111.6, 109.2, 99.4, 80.2, 64.5, 63.9, 58.1, 52.3, 43.8, 29.7; MS (ES+) m/z 443.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15]([CH3:24])=[CH:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CN(C=O)C.Cl.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>C1(C)C=CC=C(C)C=1>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15]([CH3:24])=[CH:14]2)(=[O:11])=[O:12])=[CH:3][C:2]=1[NH:1][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31]
Reactant: COc1ccc2c(c1)c(C)cn2S(=O)(=O)c1ccc(OC)c(N)c1
Reactant: CN(C)CCCl
Agent: Cl
Solvent: Cc1cccc(C)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C)cn2S(=O)(=O)c1ccc(OC)c(NCCN(C)C)c1
Temperature: 25 °C

Procedure:
1-(3′-Amino-4′-methoxy benzenesulfonyl)-5-methoxy-3-methyl-1H-indole (600 mg, 1.7 mmol) (obtained from preparation 2) was taken into a 25 mL two necked round bottom flask containing DMF (3 mL) and m-Xylene (3 mL). Added 2-dimethylamino ethyl chloride hydrochloride (490 mg, 3.4 mmol) and heated at 135° C.-138° C. for a period of 10 hours and the progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mass was cooled to room temperature, quenched into chilled water (25 mL) and pH adjusted to 9.0 to 10.0 with 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (2×50 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound. The obtained technical product was purified by column chromatography, eluent being ethylacetate and triethylamine (99:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].[NH2:17][CH2:18][CH2:19][NH2:20]>>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:17][CH2:18][CH2:19][NH2:20])(=[O:6])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Reactant: NCCN
Product: NCCNc1ccc([N+](=O)[O-])cc1S(=O)(=O)CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
132.85 g of 2-chloro-5-nitrophenyl hydroxyethyl sulfone are added at 65°-70° C. with stirring to 250 g of 1,2-diaminoethane in the course of 15 minutes, and the mixture is stirred at this temperature for a further 15 minutes. The reaction mixture is then allowed to cool down to room temperature with stirring and is poured onto 1 l of ice-water, and the product is isolated by filtration. This gives 139.6 g (2-β-aminoethylamino)-5-nitrophenyl hydroxyethyl sulfone having a melting point of 147° C. and a purity of >98%, which corresponds to a yield of 94.5% of theory, relative to starting 2-chloro-5-nitrophenyl hydroxyethyl sulfone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C@@H:9]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:10][C:11](=[O:14])[NH:12][CH3:13])=[O:6].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl-:1].[CH3:13][NH:12][C:11]([O:10][C@H:9]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:8][O:7][C:5]([CH2:4][CH2:3][CH2:2][N+:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])=[O:14]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCCCl)OC(=O)NC
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCC[n+]1ccccc1)OC(=O)NC
Product: [Cl-]

Procedure:
A solution of 0.2 g of (R)-1-O-(4-chloro-butyryl)-2-O-(methylcarbamoyl)-3-O-octadecylglycerine in 10 ml of pyridine is heated to 80° C. for 16 hours. The solution is evaporated and the residue is treated with toluene by azeotropic distillation. The residue is recrystallized from ether. There is obtained 1-[3-[[(R)-2-[(methylcarbamoyl)oxy]-3-(octadecyloxy)propoxy]carbonyl]-propyl]pyridinium chloride of melting point 53°-60° C. (dec.).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:10]=1[CH3:11].O>CO>[CH3:11][C:10]1[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[N:6][C:5]=1[O:2][CH3:1]
Reactant: C[O-]
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nnc(-c2ccccc2)cc1C
Yield: 89.9 %

Procedure:
Sodium methoxide (243 g) is cautiously added to a solution of 3-chloro-4-methyl-6-phenylpyridazine (307 g, 1.5 mol) in 3.4 L of methanol. The mixture is heated to refluxing temperature for approximately eight hours under an atmosphere of nitrogen and then poured into water (4.5 L). The resulting precipitate is collected, washed with water, and dried to give 270 g (90%) of product with a melting point of 62°-64° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)=[O:10])[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: Cc1cccc(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of 6-methylpyridine-2-carboxylic acid (5.66 g, 41.3 mmol) in tetrahydrofuran (300 mL) were added N,N-dimethylformamide (5 drops) and oxalyl chloride (7.20 mL, 83.0 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (200 mL). A solution of 5-(3-aminophenoxy)pyridin-2-amine (7.90 g, 39.3 mmol) in N,N-dimethylacetamide (20 mL) was added with stirring at room temperature, and the mixture was stirred at room temperature for 65 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (10.4 g, 83%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:28](Cl)([Cl:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Cl:30][C:28]([O:27][CH:24]1[CH2:23][CH:12]2[CH2:13][O:14][C:15]3[C:20]([C:11]2([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:26][CH2:25]1)=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])=[O:29]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCC(O)CC1COc1c(F)ccc(F)c12
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)OC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-ol (0.46 g, 1.11 mmole) was dissolved in 30 ml DCM. Phosgene (20% in toluene, 4 ml) and pyridine (1 ml) were added and the reaction was stirred at room temperature for 10 minutes. 20 ml DCM was added and the reaction was quenched by slowly adding 10 ml water. The organic layer was washed with 50 ml 1N HCl solution, dried over sodium sulfate. After the solvent was removed, the residue was purified by column using EtOAc/Hex. as the solvent (gradient from 0/100 to 25/75 in 25 minutes). Yield: 0.37 g, 70%. 1H NMR (CDCl3 400 MHz) δ 7.62 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 7.06-7.13 (m, 1H), 6.40-6.47 (m, 1H), 5.28 (dd, 1H, J=11.7 and 2.9 Hz), 5.05 (s, 1H,), 4.14 (d, 1H, J=11.7 Hz), 3.02 (dt, J=13.2 and 2.9 Hz, 1H), 2.31-2.49 (m, 2H), 2.01-2.16 (m, 2H), 1.66-1.75 (m, 1H), 1.30-1.40 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=4)[CH2:17][CH2:16]3)=[N:11][N:10]([CH3:30])[C:9]2=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.CC#N.[Pd]>[NH2:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C:12]3[N:8]([CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:9](=[O:31])[N:10]([CH3:30])[N:11]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cn1nc(CCN2CCN(c3cccc([N+](=O)[O-])c3)CC2)n(CC2CCCCC2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: CC#N
Product: Cn1nc(CCN2CCN(c3cccc(N)c3)CC2)n(CC2CCCCC2)c1=O
Yield: 98.8 %

Procedure:
A slurry of 4-(cyclohexylmethyl)-2-methyl-5-{2-[4-(3-nitrophenyl)piperazino]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (D15; 490 mg, 1.143 mmol) and 10% Pd/C (250 mg) in MeOH (30 mL) was hydrogenated in an autoclave at 30 bar and room temperature for 4 hrs. The reaction mixture was filtered over a pad of Celite and the solvent was removed in vacuo to afford a light-brown film. This was re-dissolved in MeCN (20 mL) and filtered again through a Celite plug. The solvent was evaporated in vacuo to afford 450 mg (99%) of the title compound as a brown solid.
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.[NH2:10][CH:11](C(O)=O)[CH2:12][CH2:13][CH3:14]>C(#N)C>[C:7]([C:3]1[NH:1][C:11]([CH2:12][CH2:13][CH3:14])=[N:10][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: CCCC(N)C(=O)O
Solvent: CC#N
Product: CCCc1nc(C)c(C(C)=O)[nH]1
Reaction time: 23.7 h
Yield: 32.3 %

Procedure:
An acetonitrile (250 ml) mixture of 3-oximino-2,4-pentanedione (40 g, 0.31 moles) and d,l-norvaline (43.55 g, 0.372 moles) was heated to reflux under nitrogen. After 23.7 h the reaction mixture was allowed to cool, then suction filtered. The residue was washed with acetonitrile and the combined filtrates concentrated in vacuo. After dissolving the resulting oil in ethyl acetate (100 ml), it was washed with three 40 ml portions of 5% aqueous sodium hydroxide solution. The combined organic extracts were dried over anhydrous potassium carbonate and then concentrated in vacuo to give 0.1 moles (43.5% yield based on recovered d,l-norvaline) of 5-acetyl-4-methyl-2-propylimidazole.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][N:24]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[CH3:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][N:2]2[CH2:7][CH2:6][CH:5]([C:8]3[N:13]=[C:12]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)[N:11]=[C:10]([OH:20])[CH:9]=3)[CH2:4][CH2:3]2)=[CH:25][N:24]=1
Reactant: Oc1cc(C2CCNCC2)nc(N2CCCCC2)n1
Reactant: CNc1ncc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CNc1ncc(CN2CCC(c3cc(O)nc(N4CCCCC4)n3)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A mixture of 6-piperidin-4-yl-2-piperidin-1-yl-pyrimidin-4-ol, hydrochloride salt (2.0 mmol), 2-methylaminopyrimidine-5-carbaldehyde (2.6 mmol), triethylamine (4.0 mmol) and 3 drops of acetic acid in dry dichloromethane (20 mL) was stirred at room temperature for 3 hours. Then sodium triacetoxyborohydride (6.0 mmol) was added in portions and stirring was continued for 48 hours (monitored by TLC). The mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL), and the product was extracted with dichloromethane (2×10 mL). The extracts were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give a crude product. Purification via column chromatography (silica gel, ethyl acetate/hexane) afforded 6-[1-(2-methylaminopyrimidin-5-ylmethyl)-piperidin-4-yl]-2-piperidin-1-yl-pyrimidin-4-ol (Compound IIc, 637 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Mg].[CH3:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[C:16]([CH3:18])[CH:17]=1.Cl[P:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[P:29](Cl)Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([P:22]([C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[P:29]([C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:14]2[CH:13]=[C:12]([CH3:11])[CH:17]=[C:16]([CH3:18])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: ClP(Cl)c1ccccc1P(Cl)Cl
Reactant: Cc1cc(C)cc(Br)c1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccccc2P(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Dimethylbromobenzene (5.54 g, 29.93 mmol) was added dropwise to magnesium (1.07 g, 44.03 mmol) and THF (30 mL) in an argon atmosphere. The reaction mixture was cooled to ambient temperature and filtered, and the thus-obtained THF solution of 3,5-dimethylphenylmagnesium bromide, and 1,2-bis(dichlorophosphino)benzene (0.95 g, 3.39 mmol) were reacted as in Production Example 1. The reaction was allowed to proceed overnight at 60° C. After purification, the title compound was obtained as a white powder (1.45 g, yield 76%).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[NH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([OH:30])=[C:25]([C:28]#[N:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:15][C:14]=1[F:33].O.[C:35]([O:38][CH2:39][CH3:40])(=O)C>>[NH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH2:40][C@H:39]4[CH2:35][O:38]4)=[C:25]([C:28]#[N:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:15][C:14]=1[F:33]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OC[C@H]1CO1
Temperature: 50 °C

Procedure:
After adding dimethylformamide (8 ml), p-toluenesulfonic acid (2R)-glycidyl ester (1000 mg) and potassium carbonate (940 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (1000 mg), the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (659 mg) as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH3:12]
Reactant: CCI
Reactant: Oc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(F)cc(F)c1
Yield: 62.5 %

Procedure:
To a solution of 3,5-difluoro-phenol (10.0 g, 76.87 mmol, 1.0 equiv) and iodo-ethane (28.77 g, 14.91 mL, 184.49 mmol, 2.4 equiv) in aceton (150 mL) was added portionwise potassium carbonate (31.87 g, 230.6 mmol, 3.0 equiv) and the reaction mixture heated to reflux for 6 h. The reaction mixture was filtered, the filtrate poured into ice water and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 7.60 g (63%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.41 (t, J=7.5 Hz, 3H), 3.99 (q, J=7.5 Hz, 2H), 6.36-6.43 (m, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][C:21]([F:25])([F:24])[CH2:20][CH2:19]3)=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[F:25][C:21]1([F:24])[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=3[CH:11]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc2cc(OCCN3CCC(F)(F)CC3)ccc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(OCCN3CCC(F)(F)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,4-difluoropiperidine hydrochloride (1 g, 6.3 mmol) in THF (20 mL) was added methylbromoacetate (0.63 mL, 6.6 mmol) and triethylamine (2.65 mL, 19.0 mmol). The reaction was heated at reflux for 4 h. The reaction was diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4,4-difluoropiperidin-1-yl)acetic acid methyl ester as a brown oil (1.17 g, 96%). MS 194 (M+H)+. To a solution of (4,4-dfluompiperidin-1-yl)acetic acid methyl ester (1.17 g, 6.1 mmol) in THF (15 mL) at 0° C. was added potion wise lithium aluminium hydride (0.46 g, 12.2 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4,4-difluoropiperidin-1-yl)-ethanol as a brown oil (0.99 g, 99%). MS 166 (M+H)+. To a solution of diisopropylazodicarboxylate (0.36 mL, 1.82 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (728 mg, 2.18 mmol). The reaction was stirred at RT for 10 min. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (025 g, 1.21 mmol) and 2-(4,4-difluoropiperidin-1-yl)-ethanol (210 mg, 1.27 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (375 mg, 88%). MS 354 (M+H)+. To a solution of 5-[2-(4,4-difluoropiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (375 mg, 1.06 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (34 mg, 2.12 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 326 (M+H. 5.3 min) and used for coupling onto H2N-Leu-P1 without any further purification.