Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32]C(OC)=O)[C:26]=1[C:37](=O)[CH3:38])(=[O:3])[CH3:2].[Br:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1.[OH-].[K+].Cl>C(O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:26]2[C:37](/[CH:38]=[CH:45]/[C:44]3[CH:47]=[CH:48][C:41]([Br:40])=[CH:42][CH:43]=3)=[CH:32][O:31][C:27]=2[CH:28]=[CH:29][CH:30]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1C(C)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(/C=C/c4ccc(Br)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a suspension of 2′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6′-(methoxycarbonylmethoxy)acetophenone (0.55 g) and 4-bromobenzaldehyde (0.19 g) in ethanol (9 mL) were added water (3 mL) and potassium hydroxide (0.67 g), and the mixture was stirred at room temperature for three days. To the reaction mixture was added 2 mol/L hydrochloric acid (7 mL), and the resulting mixture was extracted with ethyl acetate twice. The extracts were combined and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To the residue were added sodium acetate (1.97 g), acetic acid (5 mL) and acetic anhydride (2.08 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was cooled to room temperature and poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-3/2) to give the title compound (0.2 g).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22]Br.CS(C)=O.[OH-].[Na+]>O>[C:15]([C:14]([C:11]1[CH:12]=[CH:13][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: BrCBr
Reactant: CCCCC(C#N)c1ccc(Sc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1ccc(Sc2ccccc2)cc1
Yield: 101.5 %

Procedure:
To a mixture of 31 g (0.1 mole) of 2-(4-phenylthiophenyl) hexanenitrile, 22 g (0.13 mole) of dibromomethane and 100 ml of dimethyl sulfoxide is added 12 g (0.15 mole) of 50% sodium hydroxide solution dropwise with stirring. Reaction mixture is stirred at 60° for 1/2 hour and then poured into water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 38 g of product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:7]=12.[Li+].CC([N-]C(C)C)C.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=3)=[C:9]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:7]=12
Reactant: CC(C)(C)OC(=O)n1cc(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c21
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To solution of tert-butyl 7-chloro-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (349 mg, 0.76 mmol) in THF (15 mL) cooled to −78 C was added LDA (0.57 mL, 1.1 mmol, 2 M). After 30 min at this temperature, ethyl chloroformate (0.15 mL, 1.5 mmol) was added and the mixture was warmed to r.t. slowly. The reaction mixture was then quenched with 5% potassium bisulfate and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified on silica (gradient elution, 0-30% EtOAc/hexanes) to yield the title product (362 mg). HRMS (ESI) calc (M+H)+=529.1348. found 529.1346.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][N:6]1[C:5]([O:30][CH3:31])=[N:4][C:3]2[C:7]1=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=2[NH2:1]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3C(=O)c4ccccc4C3=O)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The product from step (vi) (1 g) was dissolved in ethanol (10 ml) and hydrazine monohydrate (1 ml) was added and stirred at ambient temperature for 10 h. The resultant was concentrated under reduced pressure and the residue suspended in DCM (10 ml) and stirred for 1 h. The suspension was filtered, washed with DCM. The solution was washed with water and dried. The solution was concentrated under reduced pressure to give the subtitled compound. Yield 700 mg.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(C(C)C)CC)(C)C.Cl.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[OH:29]>ClCCl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: N[C@@H]1CCCC[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N[C@@H]2CCCC[C@@H]2O)ccc(C#N)c1Cl
Reaction time: 4 h
Yield: 29.6 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), diisopropylethylamine (1.29 mL, 7.37 mmol), and (1S,2R)-2-aminocyclohexanol hydrochloride (670 mg, 4.42 mmol, Acros®) is microwaved using a CEM® microwave at 190° C. for 2 h and 180° C. for 4 h. The mixture is diluted with dichloromethane and washed with 1 N HCl. The aqueous layer is extracted again with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane. The isolated product is recrystallized with ether and hexane to yield the title compound as a white solid (231 mg, 29%). LC-ES/MS m/z 265.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[N:28]1)[C:25]#[CH:26]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[N:28]3)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCn1ncc2ccccc21
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Product: Cc1nnc2n1-c1ccc(C#CCn3ncc4ccccc43)cc1C(c1ccccc1F)=NC2

Procedure:
This compound was obtained as described in example 17 by reaction of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 1-(2-propynyl) 1H-indazole [ref. p. V. Tkachenko, I. I. popov, A. M. Simonov and Yu. V. Medvedov, Khim. Geterotsikl. Soedin. 11, 1542 (1975)]. The chromatographically isolated product was crystallized from ethyl acetate to give yellowish crystals with m.p. 148°-151° C.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([C:7]1[C:8]([OH:14])=[CH:9][CH:10]=[CH:11][C:12]=1O)=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(O)(=O)C>[CH3:4][C:5]1[C:7]2[C:8]([OH:14])=[CH:9][CH:10]=[CH:11][C:12]=2[NH:3][N:2]=1
Reactant: NN
Reactant: CC(=O)c1c(O)cccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1n[nH]c2cccc(O)c12
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
526 mg (10.5 mmol) of hydrazine hydrate and 1 ml of glacial acetic acid are added to 800 mg (5.26 mmol) of 2,6-dihydroxyacetophenone. After 15 minutes of stirring at 110° C., the reaction mixture is cooled to room temperature. After addition of 6 ml of polyphosphoric acid, the mixture is heated at 120° C. for 20 min. After cooling to room temperature, 0.8 g (7.89 mmol) of acetic anhydride is added dropwise. The mixture is once more heated at 120° C. for 20 min. The reaction mixture, cooled to room temperature, is then poured onto ice. The mixture is neutralized using 1N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are washed twice with water. After drying over sodium sulfate, the solvent is removed under reduced pressure. The product is purified by column chromatography. The mobile phase used is a mixture of cyclohexane and ethyl acetate (1:1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:16])[NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:16])[NH:13][C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(C)NC(=O)CC2)cc1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CC1=C(c2ccc(O)cc2)CCC(=O)N1
Yield: 36.8 %

Procedure:
A mixture containing 9 g of 3,4-dihydro-5-(4-methoxyphenyl)-6-methyl-2(1H)-pyridinone, 100 ml of collidine and 38 g of lithium iodide was heated under reflux for 28 hours and then concentrated to dryness on a rotary evaporator. The residue was dissolved in 100 ml of water and again concentrated to dryness on a rotary evaporator; this process was repeated twice to remove the last traces of collidine. The solid residue was dissolved in water and the aqueous solution acidified with concentrated hydrochloric acid. The gummy solid that separated on chilling was collected, washed with water, dried at room temperature, recrystallized from ether-isopropyl alcohol using decolorizing charcoal and then chromatographed over 100 g of silica gel using 5% methanol in ether as eluant to produce 3.1 g of 3,4-dihydro-5-(4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone, m.p. 197°-200° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][N:14]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1)[CH3:15].C(N(CC)CC)C.O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:15][N:14]([CH2:16][C:17]1[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:23][CH:24]=1)[CH3:13]
Reactant: C=Cc1ccc(CN(C)C)cc1
Reactant: CCOC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1/C=C/c1ccc(CN(C)C)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
18.8 g (82 mmol) of ethyl 2-bromobenzoate, 17.2 g (107 mmol) of 4-(N,N,-dimethylaminomethyl)styrene [sic], 20.7 g (205 mmol) of triethylamine, 0.36 g of palladium(II) acetate and 0.96 g of tri(o-tolyl)phosphine were mixed in 200 ml of dimethylformamide and, after addition of 1 ml of water, stirred at 140° C. for 3 h. The reaction mixture was then concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate and water. The organic phase was separated off, washed with water, dried and concentrated in vacuo. The residue was then recrystallized from petroleum ether. 16.1 g (63%) of the product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.[N:26]([CH:29]([CH3:31])[CH3:30])=[C:27]=[O:28]>CN(C=O)C>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[O:20])=[CH:12][C:11]=1[C:9]1[NH:10][C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[C:2]([NH:1][C:27]([NH:26][CH:29]([CH3:31])[CH3:30])=[O:28])[CH:3]=2
Reactant: CC(C)N=C=O
Reactant: Nc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)[nH]c2c1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 20 mL vial was transferred N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)furan-2-carboxamide I-1 (15 mg, 0.042 mmols) in DMF (2 mL), and the 2-isocyanatopropane (7 mg, 0.0.084 mmols, 2 eq) was added. The yellow reaction mixture was stirred at room temperature for 12 hrs. Checked via LCMS for the desired peak and found M+H (439). The reaction mixture was purified via preparative HPLC to isolate desired product (Compound 24). Yielded 7.2 mg, 0.016 mmols, 39%) of the desired compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10](=[O:18])OC3C=CC=CC=3)[N:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:5]=2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][N:31]=[C:30]2[O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].O>CS(C)=O>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([O:39][C:30]4[C:29]5[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=5)[N:33]=[CH:32][N:31]=4)[CH:41]=3)=[O:18])[N:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CC2)nn1-c1ccccc1)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CC5)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 70 °C
Yield: 32.6 %

Procedure:
A stirred mixture of phenyl 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (125 mg, 0.39 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (100 mg, 0.34 mmol) in DMSO (1 mL) was heated to 70° C. for 18 h. After cooling to rt, water (20 mL) was added. The resulting suspension was filtered and the collected solid purified via preparative silica gel thin-layer chromatography (eluting with a mixture of 10:10:1 ethyl acetate:dichloromethane:methanol) to give a solid which was triturated with diethyl ether (50 mL) to afford 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (58 mg, 33%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 7.51-7.55 (m, 6H), 7.34-7.39 (m, 3H), 7.17 (m, 1H), 6.91 (m, 1H), 6.14 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 1.86 (m, 1H), 0.86-0.88 (m, 2H), 0.65-0.67 (m, 2H); LC-MS (ESI) m/z 523 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]([C:8](=[O:23])[N:9]([CH2:20][CH:21]=C)[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=C>[Ru].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[C:8](=[O:23])[N:9]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH2:20][CH:21]=1
Reactant: C=CCN(CCCc1ccc(C)cc1)C(=O)C(=C)CCC(=O)OC
Agent: [Ru]
Solvent: ClCCl
Product: COC(=O)CCC1=CCN(CCCc2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.6 %

Procedure:
797 mg of 4-[allyl-(3-p-tolyl-propyl)-carbamoyl]-pent-4-enoic acid methyl ester (40af) (2.6 mM) prepared by the above Step 6 was added to the catalyst solution containing 180 mg of ruthenium catalyst (0.1 mM) dissolved in 200 ml of CH2Cl2 under Ar atmosphere. Then the mixture was stirred for 24 hrs at room temperature, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (1:1) as an eluant to give 391 mg of 3-[2-oxo-1-(3-p-tolyl-propyl)-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (40ag) (yield: 50%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)(=[O:3])[CH3:2].[N:16]1([CH2:22][CH2:23][OH:24])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(OC(O)C)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:19]3[CH2:20][CH2:21][N:16]([CH2:22][CH2:23][OH:24])[CH2:17][CH2:18]3)[N:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2cccnc2c(Br)n1
Reactant: OCCN1CCNCC1
Agent: CCOC(C)O
Product: CC(=O)Nc1cc2cccnc2c(N2CCN(CCO)CC2)n1
Reaction time: 0.75 h
Yield: 82.5 %

Procedure:
To a mixture of 2.66 g of 6-acetamido-8-bromo-1,7-naphthyridine and 6.51 g of 1-piperazine ethanol, 180 ml of ethoxyethanol was added. The resultant mixture was refluxed with stirring for 45 minutes. After the reaction, ethoxyethanol was distilled off under reduced pressure and chloroform was added to the residue. After thoroughly washing the chloroform solution with water, it was dried with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, followed by recrystallization from a mixed solvent of ethanol and ether to obtain 2.6 g of 6-acetamido-8-[4-(2-hydroxyethyl)-1-piperazinyl]-1,7-naphthyridine (Compound No. 22) as light yellowish crystals (yield: 82.5%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][CH:17]=[CH2:18])[C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([O:15][CH3:23])=[C:7]([CH2:16][CH:17]=[CH2:18])[C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-(2-propenyl)phenol (30 g) and potassium carbonate (13.8 g) were dissolved in acetone (300 ml) and, after addition of methyl iodide (28 g), the solution was stirred for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and water was added. The mixture was then subjected to extraction with ethyl acetate and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2-propenyl)anisole (31 g) quantitatively.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: BrCCc1ccc2c(c1)CCO2
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc3c(c2)CCO3)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)-piperidine (1.09 g), 5-(2-bromoethyl)-2,3dihydrobenzofuran (0.9 g--see Preparation 5), anhydrous potassium carbonate (1.1 g) and acetonitrile (25 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.64 g, m.p. 137-140° C., [α]D25 +13.7° (c, 1.0, CH2Cl2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(Cl)(Cl)Cl>[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:19])[CH3:18]
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 11.9 g of indoline in 100 ml of chloroform is cooled to 0° C., 13.9 ml of triethylamine are added and a solution of 10.4 ml of acetic anhydride in 10 ml of chloroform is then added dropwise, followed by 0.1 g of 4-dimethylaminopyride. After stirring for two hours at RT, water is added to the reaction mixture, extraction is carried out with chloroform, the organic phase is dried over sodium sulfate and the solvent is evaporated off under vacuum to give 15.44 g of the expected product, which is used as such.
Reaction SMILES: [CH3:1][N:2]([S:36]([CH3:39])(=[O:38])=[O:37])[C:3]1[C:8]([CH2:9][NH:10][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([P:28](=[O:35])([O:32]CC)[O:29][CH2:30][CH3:31])=[CH:24][CH:23]=3)[N:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl>>[CH3:1][N:2]([S:36]([CH3:39])(=[O:38])=[O:37])[C:3]1[C:8]([CH2:9][NH:10][C:11]2[C:16]([C:17]([F:18])([F:19])[F:20])=[CH:15][N:14]=[C:13]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([P:28](=[O:32])([OH:35])[O:29][CH2:30][CH3:31])=[CH:26][CH:27]=3)[N:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOP(=O)(OCC)c1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1
Agent: Cl
Product: CCOP(=O)(O)c1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1

Procedure:
Diethyl [4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]phosphonate (Example 2) in an excess of concentrated HCl (37%) and heated at 80° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC (MDP) to afford the title compound (Example 40). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=6.9 Hz, 3H), 3.16 (s, 6H), 3.81 (ddd, J=14.7, 7.3, 7.1 Hz, 2H), 4.83 (d, J=5.6 Hz, 2H), 7.34-7.45 (m, 3H), 7.55 (dd, J=8.2, 3.2 Hz, 2H), 7.64-7.73 (m, 2H), 8.31 (d, J=0.8 Hz, 1H), 8.45 (dd, J=4.7, 1.9 Hz, 1H), 9.86 (s, 1H); MS (UPLC TOF): m/z 562.14 [MH+]; HPLC: tR=1.15 min (polar-3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: Nc1ccnc(Cl)c1
Product: Nc1ccnc(N2CCCC2)c1
Temperature: 200 °C
Yield: 79 %

Procedure:
A mixture of 2-chloro-4-aminopyridine 109 (2.29 g, 17.8 mmol) and pyrrolidine 68 (5.0 mL) was heated at 200° C. in a microwave reactor for 10 min. After cooling to room temperature, the solid was filtered and washed with dichloromethane (10 mL×3). The filter cake was dissolved in aqueous K2CO3 and extracted with CH2Cl2 (40 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to obtain 110 (2.30 g, 79% yield).