Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C=O.[C:20]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]1[C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:20])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: [BH3-]C#N
Reactant: Cc1c(OC2CCCNC2)ccc2[nH]ncc12
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(OC2CCCN(C)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
Acetic acid (0.060 ml) was added to a methanolic solution (1.0 ml) of the 4-methyl-5-(piperidin-3-yloxy)-1H-indazole (46 mg, 0.20 mmol) obtained in Example 422, followed by adding thereto paraformaldehyde (30 mg, 1.0 mmol), and the resulting mixture was stirred at room temperature for 2 hours. Then, a solution of sodium cyanoborohydride (63 mg, 1.0 mmol) in methanol (1.0 ml) was added thereto and the resulting mixture was stirred at room temperature for 18 hours. After a 1N-aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate/triethylamine=5/15/1) to obtain 4-methyl-5-[(1-methylpiperidin-3-yl)oxy]-1H-indazole (34 mg, 70%).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 259 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (224 mg) in THF (4.0 mL) and methanol (2.0 ml) was added 1N aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (4.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (549 mg) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:21]2[C:29]3[C:24](=[C:25]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[CH:32][C:31]=4[CH3:38])[CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].[CH2:46]([S:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OC(C)C)(C)C>[CH2:46]([S:48][CH2:49][CH2:50][O:37][C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:24]=2[CH2:23][CH2:22][CH:21]3[N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:2]([F:1])[CH:7]=2)=[C:31]([CH3:38])[CH:32]=1)[CH3:47]
Reactant: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(O)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CCSCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(OCCSCC)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.00 g, 1.58 mmol), 2-(ethylthio)ethanol (0.219 mg, 2.06 mmol) and tributylphosphine (0.417 mg, 2.06 mmol) in tetrahydrofuran (25 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.520 g, 2.06 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. The reaction mixture was diluted with diisopropyl ether, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (1.06 g, yield 93%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:3]2[C:2]([C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][C:34]=3[Cl:36])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Temperature: 100 °C
Yield: 51.5 %

Procedure:
To a degassed solution of 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.02 mmol), 2,4-dichlorophenylboronic acid (8.0 mg, 0.041 mmol) and K2CO3 (8.5 mg, 0.061 mmol) in 1,4-dioxane (0.3 mL) and H2O (0.1 mL) was added Pd(PPh3)4 (2.3 mg, 0.002 mmol) under argon at 20° C. The reaction mixture was heated at 100° C. for 2 h under argon, then allowed to cool to 20° C. The reaction was concentrated in vacuo, and the residue was purified using reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μC18 30×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm) to afford 5.5 mg (55%) of the title compound as a white solid. LC/MS (method B): retention time=2.03 min, [M+H]+=533.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](=O)[CH2:11][Br:12].[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[NH:16])[NH2:15]>>[BrH:12].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[N:20]=[C:18]([NH:17][C:14]([NH2:16])=[NH:15])[S:19][CH:11]=1
Reactant: N=C(N)NC(N)=S
Reactant: O=C(CBr)c1cc2ccccc2[nH]1
Product: Br
Product: N=C(N)Nc1nc(-c2cc3ccccc3[nH]2)cs1
Yield: 80.4 %

Procedure:
By reaction of 1.31 g (5.48 mmole) 1-(1H-indol-2-yl)-2-bromoethanone with 0.65 g (5.53 mmole) guanylthiourea by the method of Example 10 afforded 1.49 g (80%) of the title salt; m.p. 309°-310° C. (decomp.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2]1.C=O.[BH3-][C:16]#N.[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[CH3:16][N:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2]1
Reactant: [BH3-]C#N
Reactant: c1cncc(O[C@@H]2CCNC2)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@@H](Oc2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To 164 mg (1 mmol) of 3-(3-(R)-pyrrolidinyloxy)-pyridine were added 300 mg (10 mmol) of paraformaldehyde, 314 mg (5 mmol) of NaCNBH3, and 5 mL of dry THF at room temperature. To the suspension was added 2 mL of trifluoroacetic acid dropwise. The suspension was allowed to stir at room temperature overnight. Next day, to the suspension was slowly added a mixture containing 20 mL of 4N NaOH and ice-chips. The mixture was then extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (15:1, CHCl3:MeOH) to obtain 9 mg (5%) of a clear oil: 1H NMR (300 MHz, CD3OD) δ 8.19 (1H, d, J=1.7 Hz), 8.12 (1H, m). 7.38 (2H, m), 4.99 (1H, m), 2.94-2.80 (3H, m), 2.52-1.93 (3H, m), 2.40 (3H, s); Mass spectrum (ESI) m/z 179.4 (M+H+).
Reaction SMILES: [C:1]([O-])(=[O:6])CCCC.[CH:8](=[O:12])[CH:9]([CH3:11])[CH3:10].CO[C:15]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([CH3:18])[CH3:17].C(OCC)(=O)C>O1CCCC1>[CH3:10][C:9]([CH3:11])([CH:15]([O:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:16]([CH3:17])[CH3:18])[C:8]([O:6][CH3:1])=[O:12]
Reactant: CC(C)C=O
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CCCCC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)C(O[Si](C)(C)C)C(C)C
Reaction time: 18 h
Yield: 97 %

Procedure:
In another preparation of the aforesaid valerate, isobutyraldehyde (0.72 g) was added to a mixture of [(1-methoxy-2-methyl-1-propenyl)oxy]trimethylsilane (1.74 g, 10 mmol) and (TAS)HF2 (100 mg, 0.1 mmol) in 20 mL of tetrahydrofuran under argon at -11°. The reaction mixture was stirred and the temperature was allowed to rise to 23°. Stirring was continued for 18 h and the mixture was then poured into 200 mL of ethyl acetate and extracted with water (200 mL), followed by washing with aqueous brine (200 mL). The organic layer was dried (MgSO4), filtered and evaporated in vacuo to give 2.39 g (97% yield) of methyl 2,2,4-trimethyl-3-trimethylsiloxyvalerate.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.[Br:25][C:26]1[S:30][C:29]([CH2:31]O)=[CH:28][CH:27]=1>CN(C)C=O>[Br:25][C:26]1[S:30][C:29]([CH2:31][N:20]2[CH:19]=[C:18]([Cl:17])[CH:23]=[N:22][C:21]2=[O:24])=[CH:28][CH:27]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: OCc1ccc(Br)s1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1Cc1ccc(Br)s1
Temperature: 40 °C
Yield: 45.2 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (2.25 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (653 mg) and 5-bromo-2-hydroxymethylthiophene (1.351 g) in dry N,N-dimethylformamide (12.5 ml) under nitrogen and then the mixture was heated at 40° C. After 2 h the temperature was increased to 80° C. After 4 h the reaction mixture was evaporated to dryness and the residue triturated with diethyl ether. The solid was collected and crystallised from acetone to give off white crystals of the title pyrimidinone (691 mg), m.p. 217°-220° C., λmax (EtOH) 243.5 nm (ε 13,810), 336 nm (ε 1,190).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)C=O.[CH:12](OC)([O:15][CH3:16])[O:13][CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:5]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH:4]=1
Reactant: COC(OC)OC
Reactant: Cc1cc(C=O)cc(CBr)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(OC)c1cc(C)cc(CBr)c1
Temperature: 25 °C

Procedure:
A mixture of crude 3-bromomethyl-5-methyl-benzaldehyde (21 g, 98.51 mmol), trimethyl orthoformate (21.88 ml), and p-toluenesulfonic acid monohydrate (1.9 g) in anhydrous methanol (100 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was dissolved in ether, washed with aqueous sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a pale brown oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 7.6 g (29% for 2 steps) of a colorless oil. 1H NMR (300 MHz, CDCl3) δ 2.35 (3H, s), 3.33 (6H, s), 4.47 (2H, s), 5.32 (1H, s), 7.17 (1H, s), 7.19 (1H, s), 7.27 (1H, s).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:20]=[CH2:21])[CH:16]=3)[NH:11][C:10]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+]>C(#N)C>[O:47]=[C:40]1[O:39][N:38]=[C:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:11]3[C:12]4[C:17](=[CH:16][C:15]([CH:20]=[CH2:21])=[CH:14][CH:13]=4)[C:18](=[O:19])[N:9]([CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:10]3=[O:22])=[CH:26][CH:27]=2)[NH:41]1
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: C=Cc1ccc2[nH]c(=O)n(CCc3ccccc3)c(=O)c2c1
Agent: [K+]
Solvent: CC#N
Product: C=Cc1ccc2c(c1)c(=O)n(CCc1ccccc1)c(=O)n2Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 3-(2-phenylethyl)-6-vinylquinazoline-2,4(1H,3H)-dione (0.40 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.65 g), potassium carbonate (0.38 g) and acetonitrile (16 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and acetone (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and extracted with chloroform. The obtained chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 57%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:27]([CH2:28][C:29]#N)=[CH:26][CH:25]=[CH:24][N:23]=2)[O:17][N:16]=1.[OH-:31].[Na+].C(O)C.Cl.[OH2:37]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:27]([CH2:28][C:29]([OH:37])=[O:31])=[CH:26][CH:25]=[CH:24][N:23]=2)[O:17][N:16]=1
Reactant: [OH-]
Reactant: O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2CC#N)on1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2CC(=O)O)on1
Yield: 77 %

Procedure:
A mixture of 2-[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrile (1.02 g), a 2N aqueous sodium hydroxide solution (10 mL) and ethanol (20 mL) was heated under reflux for 5 hrs. Water was added to the reaction mixture, and the mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals (820 mg, 77%) of 2-[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetic acid. Recrystallization from ethyl acetate-isopropyl ether gave colorless needle crystals. melting point: 129-130° C.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:4](=[O:7])[NH:5][N:6]=1.Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:5]1[C:4](=[O:7])[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:2]([Br:1])=[N:6]1
Reactant: O=c1[nH]nc(Br)n1Cc1ccccc1F
Reactant: COC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)Cn1nc(Br)n(Cc2ccccc2F)c1=O

Procedure:
300 mg (1.1 mmol) of the compound from Example 135A are stirred under reflux for 2 hrs together with 150 mg (1.38 mmol) of methyl chloroacetate and 168 mg (1.21 mmol) of potassium carbonate in 10 ml acetonitrile. After cooling, the mixture is diluted with ethyl acetate and treated with 1 N hydrochloric acid. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulphate and freed of the volatile components on the rotary evaporator. The residue is dried under high vacuum. The product thus obtained (360 mg, purity ca. 73% by LC/MS) is used in the next synthetic step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23]2)=[CH:20][CH:21]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[ClH:1].[ClH:30].[ClH:1].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[CH:20][CH:21]=2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC(N(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC(N(C)C)C2)nc1
Product: Cl
Yield: 173.1 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{6-[3-(dimethylamino)pyrrolidin-1-yl]-pyridin-3-ylamino}-1,5-naphthyridin-3-yl)ethanone (55 mg, 0.134 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58 mg, 0.20 mmol) followed by formation of the trihydrochloride salt to afford the desired product (75 mg, 86%) as an orange solid: 1H NMR (300 MHz, CD3OD) δ 9.41 (s, 1H), 8.55-8.38 (m, 2H), 8.30 (d, J=2.4 Hz, 1H), 7.97 (dd, J=9.5, 2.4 Hz, 1H), 7.54 (s, 2H), 7.05 (d, J=9.5 Hz, 1H), 4.20-4.16 (m, 2H), 4.02-3.86 (m, 2H), 3.80-3.70 (m, 1H), 3.03 (s, 6H), 2.85 (s, 3H), 2.82-2.68 (m, 1H), 2.39-2.52 (m, 1H); ESI MS m/z 537 [M+H]+; HPLC>99% (AUC), tR=9.08 min.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[S:24](=[O:26])=[O:25].[ClH:27]>O.C(O)(=O)C>[CH3:22][C:12]1[C:11](=[O:23])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:24]([Cl:27])(=[O:26])=[O:25])[C:15]=2[O:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S=O
Reactant: Cc1c(-c2ccccc2)oc2c(N)cccc2c1=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(S(=O)(=O)Cl)cccc2c1=O
Reaction time: 0.5 h

Procedure:
A solution of 4.55 g of sodium nitrite in 12 ml of water was added dropwise to a stirred mixture of 15.1 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re, P. et al., Il. Farmaco (Ed. Sci.) 11: 670, 1956) in 150 ml of hydrochloric acid (d=1.18) at -5° C. Stirring was continued at 0° C. for 30 minutes. The solution was poured, over a period of 10 minutes and at -5° to 0° C., into 120 ml of a 30% by weight solution of sulfur dioxide in acetic acid containing 1.53 g of cupric chloride dihydrate and 13 ml of water. After 1 hour at 0° C. and 1 hour at 20°-25° C., 300 ml of iced water was added to the mixture. A precipitate formed and was collected by suction filtration, washed with water and dried in a desiccator over sodium hydroxide until of constant weight to give 18 g of crude title product, m.p. 165°-170° C., for use without further purification.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:20][O:21]C(=O)C)[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=O)C.[OH2:25].[OH-].[Na+]>C(O)=O>[OH:4][CH2:5][CH:6]([CH2:20][OH:21])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:25])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2.[CH:17]1[N:9]([CH2:8][CH2:7][CH:6]([CH2:20][OH:21])[CH2:5][OH:4])[C:10]2[N:11]=[C:12]([NH2:19])[N:13]=[C:14]([OH:25])[C:15]=2[N:16]=1
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Nc1nc(O)c2ncn(CCC(CO)CO)c2n1
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Temperature: 42.5 °C

Procedure:
A mixture of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine (10 g, 28.1 mmole), formic acid (96%. 6.3 ml) and water (55 ml) was stirred and heated to reflux for about 4 hours. After cooling the solution was basified by mixing with sodium hydroxide solution (12.5M, 27 ml) and the resulting solution was stirred for 1.5 hrs. The solution was neutralised by the addition of formic acid. The resultant slurry was heated to reflux (ca 105° C.) then cooled to 40-45° C. and stirred for about 3 hours. The crude product is then isolated and washed with water (20 ml). The isolated product was dissolved in sodium hydroxide solution (3M, 80 ml). Carbon (ca 1.5 g) was added and the slurry stirred for about 1 hr then the carbon was removed by filtration and washed with water (20 ml). The solution was neutralised by the addition of formic acid and the resultant precipitate was redissolved by heating to ca 100° C. and was then cooled. The precipitated product was stirred for about 3 hrs then isolated and washed with water (2×20 ml) before being dried.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9]Br.O.O.OC[S:15]([O-:17])=[O:16].[Na+].O>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH2:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][S:15](=[O:16])[O:17]1
Reactant: BrCc1ccccc1CBr
Reactant: O=S([O-])CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: O=S1Cc2ccccc2CO1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 1,2-bis(bromomethyl)benzene (15 g, 56.8 mmol) in N,N-dimethylformamide (100 mL) at 0° C. was added tetrabutylammonium bromide (3.66 g, 11.4 mmol), followed by sodium hydroxymethane sulfinate dihydrate (17.5 g, 113.6 mmol) in one portion. The resulting suspension was stirred at 0° C. for 7 h under nitrogen and then at room temperature for 10 h. Water (250 mL) was added and after 30 min the reaction mixture was diluted with diethyl ether. The organic layer was washed with water twice. The aqueous layer was extracted with diethyl ether twice more. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated under vacuum to yield the title compound (purity 80%). 13C NMR (400 MHz, CDCl3) δ 133.8, 130.0, 128.6, 127.9, 125.9, 125.7, 63.0, 57.0. 1H NMR (400 MHz, CDCl3) δ 7.20-7.41 (m, 4H), 5.31 (d, J=13.6 Hz, 1H), 4.97 (d, J=13.6 Hz, 1H), 4.42 (d, J=15.4 Hz, 1H), 3.56 (d, J=15.4 Hz, 1H). MS [M+H]+, 169.