Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:24][C:23]=2[F:39])=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:24][C:23]=3[F:39])=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
To a solution of benzyl (4-{[1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl]oxy}-3-fluorophenyl)carbamate (28.0 g, 49.6 mmol) in tetrahydrofuran (280 mL) was added trifluoroacetic acid anhydride (196 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, ethanol (140 mL) and 4N aqueous sodium hydroxide solution (40 mL) were added to the residue, and the mixture was stirred at room temperature for 4 hr. The solvent was concentrated under reduced pressure to about 1/3, water was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/0→9/1) to give the title compound (10.0 g, 51%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].B(O)O>>[C:26]([O:25][C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:34][CH:33]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and [4-(N-Boc-aminomethyl)phenyl]boronic acid as a boronic acid, 4-(4-tert-butoxycarbonylaminomethyl-phenyl)-2-(morpholin-4-yl)-7-(pyridin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained. This was dissolved in 1N hydrochloric acid-acetic acid, followed by stirring at room temperature for 40 minutes, and diethyl ether was added to the reaction mixture, to filter off a solid, whereby the desired compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[CH:30]1([NH:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNC4CCCCC4)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15g) and cyclohexylamine (0.17ml) in dimethylformamide (10ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanolhexane to give N-(4-((cyclohexylamino)methyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 114) (0.09g) as colorless crystals.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][CH2:5][CH:6]([O:9][CH2:10][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:14]=[C:13]([C:32](=[O:34])[CH3:33])[CH:12]=1)[CH2:7][F:8].[Cl-].[NH4+]>C1COCC1>[F:8][CH2:7][CH:6]([O:9][CH2:10][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:14]=[C:13]([C:32]([OH:34])([CH3:1])[CH3:33])[CH:12]=1)[CH2:5][F:4]
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2nc(COC(CF)CF)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COC(CF)CF)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of methylmagnesium bromide (0.71 mL, 1.0 mmol) in THF (6 mL) was added over 5 min a solution of 1-(6-((1,3-difluoropropan-2-yloxy)methyl)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)pyrimidin-4-yl)ethanone (43 mg, 0.1 mmol) of in THF (3 mL). The reaction was stirred at 0° C. for 30 minutes. Ammonium chloride (sat, aq) was added. The solvent volume was reduced by evaporation. DCM was added and the phases were separated. The organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound as a dry film (34 mg, 76%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH2:28][C:29]([OH:31])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:33][NH:34][O:35][CH3:36].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:34]([O:35][CH3:36])[CH3:33])=[O:31])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cc(Cl)ccc1OCc1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cc1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (8.6 g) was added to a solution of (2-benzyloxy-5-chlorophenyl)-acetic acid (10.6 g), N,O-dimethylhydroxylamine hydrochloride (4.4 g), 1-hydroxybenzotriazole (6.9 g) and N,N-diisopropylethylamine (20 ml) in DMF (150 ml) and the mixture stirred at RT for 16 h, then partitioned between ethylacetate and water. The organics were washed with 2M hydrochloric acid, water, dried, and evaporated under reduced pressure. Yield 12.2 g
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].F[B-](F)(F)F.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O.C(O)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([Br:1])[C:7]([N:26]=[N:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)=[N:6][CH:5]=1
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Reactant: Oc1cncc(Br)c1
Agent: F[B-](F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N=Nc2ncc(O)cc2Br)cc1
Reaction time: 1 h
Yield: 33.7 %

Procedure:
5-bromo-3-pyridinol (8.7 g, 0.05 mol) and potassium hydroxide (Fisher Scientific) were dissolved in water (200 ml). A suspension of p-nitrobenzenediazonium tetrafluoroborate (J. Org. Chem., Vol. 44, No. 9. 1979 p 1572-1573) (11.845 g, 0.5 mol) was added, and the mixture was stirred for 1 hour, diluted with acetic acid (50 ml) and filtered. The crude product was allowed to dry in air, then was chromatographed (silica gel; CHCl3 /MeOH, 95:5 to 90:10) provided 5.45 g (33.7%) of the title compound. MS (DCI/NH3) m/e 323-325 (M+H)+. 1H NMR (D6DMSO, 300 MHz) δ: 8.48-8.43 (m, 2H), 8.21-8.20 (d, J=2.37 Hz, 1H), 8.09-8.06 (m, 2H), 7.72-7.71 (d, J=2.37 Hz, 1H)
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH3+:10])=[CH:5][CH:4]=1.[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCCC1.O.[Cl-].[Na+].O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:14](=[O:15])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [NH3+]Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(Br)cc1)OCc1ccccc1
Reaction time: 1 h
Yield: 102.9 %

Procedure:
In a 500 mL round bottomed flask, equipped with a magnetic stir bar, (4-bromophenyl)methanaminium chloride (10.0 g, 44.9 mmol) and sodium hydroxide (4.00 g, 100 mmol) were dissolved in tetrahydrofuran (80 mL) and water (80 mL). The solution was cooled in an ice water bath, and benzyl chloroformate (7.06 mL, 49.4 mmol) was added dropwise. The reaction was allowed to stir for 1 hour. The reaction was poured into a brine solution and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound as a white solid (14.8 g, 102%): 1H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J=6.0 Hz, 1H), 7.64-7.53 (m, 2H), 7.47-7.33 (m, 5H), 7.32-7.20 (m, 2H), 5.10 (s, 2H), 4.23 (d, J=6.2 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 156.33, 139.20, 137.05, 131.10, 129.22, 128.33, 127.72, 119.77, 65.42, 43.19; ESIMS m/z 320, 322 ([M+H]+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][O:16][C:12]=3[C:11](=[O:17])[C:10]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.[Cu]=O>[C:23]1([N:22]2[C:18]([C:10]3[C:11](=[O:17])[C:12]4[O:16][CH:15]=[CH:14][C:13]=4[N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH:33]=[CH:32][CH:31]=[N:30]5)=[CH:3][CH:4]=4)[N:9]=3)=[CH:19][CH:20]=[N:21]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1cn[nH]c1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(I)cc2)c2ccoc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2)c2ccoc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 36.6 %

Procedure:
A suspension of 1-(4-iodophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)furo[3,2-c]pyridazin-4(1H)-one (200 mg), pyrazole (57 mg), copper oxide (6 mg), 2-hydroxybenzaldehydeoxime (23 mg) and cesium carbonate (271 mg) in DMF (5 mL) was stirred at 50° C. for 12 hr, and water was added. The reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (64 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(OCC)C>[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH:23]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14]
Reactant: CN1CCNCC1
Reactant: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21
Solvent: CCOCC
Product: CN1CCNCC1CCCCCCCCc1cccc2c1C(=O)NC2=O

Procedure:
8-Bromooctylphthalimide (516 mg; 2.0 mmoles) and N-methylpiperazine (0.44 ml; 4.0 mmoles) were dissolved to anhydroius ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.[C:27]([O-])(=[O:31])[C@H:28]([CH3:30])[OH:29].[Na+]>CN(C=O)C>[OH:29][C@@H:28]([CH3:30])[C:27]([N:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1)=[O:31]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Reactant: C[C@H](O)C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(C(=O)[C@H](C)O)C3)cc1-2

Procedure:
Following the procedure for 318, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and sodium L-lactate were reacted in DMF to give 359. LCMS: RT=10.69 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.36 (1H, s), 7.90 (1H, s), 7.20-7.11 (1H, m), 7.09-7.01 (1H, m), 5.84-5.75 (1H, m), 4.62-4.30 (4H, m), 4.26-4.07 (3H, m), 3.98-3.87 (1H, m), 3.43-3.35 (2H, m), 1.61 (6H, d, J=6.65 Hz), 1.32 (3H, dd, J=10.70, 6.64 Hz). 1 Exchangeable not observed
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:53][CH2:54][CH2:55][C:56]#[N:57].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:56]([CH2:55][CH2:54][CH2:53][O:51][C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=1)[CH2:39][N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]([C@@H:7]1[C@@H:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[Cl:31])=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]1)=[O:6])#[N:57]
Reactant: N#CCCCBr
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.2 M) was added 4-bromobutanenitrile (1.2 eq.) and cesium carbonate (1.3 eq.). The reaction was stirred at rt for 18 h, then heated to 65° C. for 4 h. After cooling to rt, the reaction was diluted with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NH4Cl solution, 5% aqueous HCl, saturated aqueous NaHCO3 solution, and brine. The organic solution was dried over MgSO4 and concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH:31]=[O:32])=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[OH:32][CH:31]([C:29]1[O:30][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:34])([F:18])[F:33])[CH:21]=2)=[CH:27][CH:28]=1)[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)c2ccc(-c3cccc(C(F)(F)F)c3)o2)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Ethyl 4-iodobenzoate (0.55 g) was dissolved in tetrahydrofuran (5 mL), and the mixture was cooled to −40° C. Isopropylmagnesium chloride (2M tetrahydrofuran solution, 1.0 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 min to prepare Grignard reagent. A solution of the compound (0.40 g) obtained in Example 222a in tetrahydrofuran (5 mL) was cooled to −40° C., and the prepared Grignard reagent solution was added. After stirring at −40° C. for 30 min, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.26 g) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:18][CH2:19][CH3:20])(=[O:17])[C:8]1[CH:16]=[CH:15][C:13]([OH:14])=[C:10]([O:11][CH3:12])[CH:9]=1.CS(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O.C(OCC)C>CN(C)C=O>[F:28][C:27]([F:30])([F:29])[CH2:26][O:14][C:13]1[CH:15]=[CH:16][C:8]([C:7]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC(F)(F)F)c(OC)c1
Temperature: 120 °C
Yield: 51.5 %

Procedure:
Potassium carbonate (62.2 g, 450 mmol) was added to a solution of ethyl vanillate (58.9 g, 300 mmol) in dimethylformamide (400 ml) and the reaction heated to 120° C. 2,2,2-Trifluoroethyl methanesulphonate (63.4 g, 360 mmol) was added over 15 minutes and the reaction heated at 120° C. for 15 hours. The reaction was cooled to ambient temperature, diethyl ether (400 ml) was added and the reaction was filtered. The filtrate was evaporated in vacuo and the residue was taken up in a mixture of diethyl ether (375 ml) and isohexane (375 ml). The organic layer was concentrated in vacuo to a total volume of 250 ml and the solid which crystallised out was collected by suction filtration. Drying of the solid in vacuo yielded ethyl 4-(2,2,2-trifluoroethoxy)-3-methoxybenzoate (43.0 g, 52% yield) as a white crystalline solid:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[CH:7][C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1.[Cl-].[Na+].[O:20]1[CH2:24]C[CH2:22][CH2:21]1>CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][C:10]1[S:9][C:8]([CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][CH2:22][CH:21]2[O:20][CH2:24]2)=[N:12][N:11]=1
Reactant: Cc1nnc(C=Cc2ccccc2O)s1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.72 g (0.085 mole) of 55% strength sodium hydride in paraffin oil are suspended in 150 ml of absolute tetrahydrofuran and 18.6 g (0.085 mole) of 2-(2-hydroxystyryl)-5-methyl-1,3,4-thiadiazole in 200 ml of absolute hexamethylphosphotriamide are then added dropwise in the course of 1.5 hours at from 0° to 3° C. Stirring is continued at room temperature for 1 hour, after which 11.7 g (0.085 mole) of dibromohydrin are added dropwise. The solution is left to stand at room temperature for 16 hours, after which it is poured onto 1.5 liters of ice water and 0.5 liter of saturated sodium chloride solution. The precipitated solid is filtered off and recrystallized from acetone. 11.8 g (51% of theory) of yellow crystals, of melting point 134°-135° C. are obtained.
Reaction SMILES: C([Mg]Br)C.[CH2:5]([OH:9])[CH2:6][C:7]#[CH:8].Cl[Si:11]([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:8]#[C:7][CH2:6][CH2:5][OH:9]
Reactant: C#CCCO
Reactant: C[Si](C)(C)Cl
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 2 mol of ethyl magnesium bromide (2.0 molar solution in tetrahydrofuran) is cooled in an ice bath and a solution of 50.5 g of 3-butyn-1-ol (0.72 mol) in 50 ml of tetrahydrofuran is slowly added. After addition is complete, the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then cooled in an ice bath and 254 ml (2 mol) of chlorotrimethylsilane was slowly added. This mixture was heated under reflux for two hours and then cooled to 20° C. and 800 ml of 1.4M aqueous sulfuric acid were added. The mixture was extracted with diethyl ether and the ether solution was dried and concentrated under vacuum. The residue was distilled to yield 72.8 g of 4-trimethylsilyl-3-butyne-1-ol, bp 43°-48° C. at 1 mm Hg.
Reaction SMILES: C([O:4][C@@H:5]([CH3:28])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:26]3[C:25]4[N:24]=[C:23]([Cl:27])[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(=O)C.[Li+].[OH-]>C1COCC1.CO>[Cl:27][C:23]1[CH:22]=[CH:21][C:20]2[N:19]=[CH:18][C:17]3[N:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C@@H:5]([OH:4])[CH3:28])[CH2:9][CH2:10]4)[C:26]=3[C:25]=2[N:24]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-yl acetate (1.2 g, 2.97 mmol) in a mixture of THF (30 mL) and MeOH (30 mL), was added LiOH (650 mg, 14.9 mmol) drop-wise. The mixture was stirred at room temperature for 3 h. After concentration in vacuo, the residue was diluted with water and the pH was adjusted to 7 with 2N HCl. The resulting mixture was concentrated and the precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one as yellow solid. The crude product was used in next step without further purification. (918 mg, yield 85.4%). MS (m/z): 361 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([Cl:19])[C:9]=2[C:8]1=[O:22].[H-].[Na+].[CH3:34]I>CN(C)C=O.C(OCC)(=O)C>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([C:2]([F:30])([F:1])[F:31])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:34])[C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([Cl:19])[C:9]=2[C:8]1=[O:22]
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c2c(n1)N(C)CCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 7; 1.50 g) was dissolved in N,N-dimethylformamide (6 mL). To this solution, sodium hydride (185 mg, 60% oil suspension) was added and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.4 mL) was then added and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column-chromatography (ethyl acetate:hexane=1:1) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-10-methyl-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (1.36 g, 88%).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C(O)C>ClCCl>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)(C)O)cc1

Procedure:
2-hydroxy isobutyric acid (1.56 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a). The title compound (2.65 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.45.