Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:15][C:16]1[C:21]([C:22]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[N:6]=[CH:5][N:4]=[C:3]3[N:2]([CH3:14])[CH3:1])=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:18][CH:17]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CN(C)c1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)c1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 19 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4,N4-dimethylquinazoline-4,8-diamine (Intermediate-54, 100 mg, 0.53 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 184 mg, 0.64 mmol), oxalyl chloride (203 mg, 1.6 mmol), DMF (1 drop) and DIPEA (344 mg, 2.67 mmol) in CH2Cl2 (2 mL) to afford 46 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ10.43 (s, 1H), 8.70-8.68 (d, J=7.6 Hz, 1H), 8.50 (s, 1H), 8.14-8.11 (t, J=5.6 Hz, 1H), 7.95-7.93 (d, J=8.4 Hz, 1H), 7.51-7.47 (t, J=8.0 Hz, 1H), 7.41-7.39 (d, J=8.4 Hz, 1H), 7.36-7.32 (t, J=8.0 Hz, 1H), 4.31-4.29 (d, J=5.6 Hz, 2H), 3.35 (s, 3H), 3.31 (s, 3H), 1.13 (s, 9H); MS (m/z): 458.22 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:23]([C:25](=[O:36])[CH2:26][C:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[O:29][CH:28]=2)[CH3:24])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)[CH:10]=1)(C)(C)C.Cl.C(OCC)(=O)C>ClCCl.O>[O:29]1[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:27]([CH2:26][C:25]([N:23]([CH3:24])[CH:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:37])=[O:5])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)=[O:36])=[CH:28]1
Reactant: CN(C(=O)Cc1coc2ccccc12)C(CN1CCC(O)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)Cc1coc2ccccc12)C(CN1CCC(O)C1)c1cccc(OCC(=O)O)c1
Reaction time: 24 h

Procedure:
To a solution of Example 27 (0.79 g, 1.55 mmol) in dichloromethane (12 mL) and water (0.5 mL) was added HCl (2.5 mL of 4 M solution in dioxan). After stirring for 24 hours, all volatiles were removed in vacuo to give a pale pink solid. The solid was stirred with ethyl acetate (75 mL) for 2 hours, then the solvent removed by pipette. This was repeated. The resulting solid was dissolved in acetonitrile (50 mL) and all solids removed by filtration. Ethyl acetate was added until the solution became cloudy, and the precipitate was allowed to settle. All supernatant was then removed and the resulting solid dried. Yield 0.25 g.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I-:13].[Cs+].B(F)(F)F.CCOCC>C(#N)C>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][I:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)Oc1ccc(CO)cc1
Agent: FB(F)F
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)Oc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-acetoxybenzyl alcohol (0.332 g, 2 mmol), and cesium iodide (0.571 g, 2.2 mmol) in anhyd. acetonitrile (10 mL) under nitrogen, boron trifluoride etherate (0.28 mL, 2.2 mmol) in acetonitrile (5 mL) was introduced. After stirring overnight, the reaction mixture was poured into ice-cold water (20 mL) and the solid separated was filtered, washed with water and later with hexanes. The product was dried under high vacuum. Yield, 0.39 g, 71%; TLC, hexanes:EtOAC (4:1). 1H NMR (CDCl3): δ 2.3 (s, 3H), 4.35 (s, 2H), 7.05 (d, 2H), 7.5 (d, 2H).
Reaction SMILES: [Li]N1C(C)(C)CCC[C:3]1(C)C.CC1CCCN(C)C1(C)C.CN(CCN(C)C)C.[Li]CCCC.[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[CH:48][C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CI>C1COCC1>[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[C:48]([CH3:3])[C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: [Li]N1C(C)(C)CCCC1(C)C
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Agent: CC1CCCN(C)C1(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: -40 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (227.2 mg, 1.62 mmol), TMEDA (188.3 mg, 1.62 mmol) and n-BuLi (1 mL, 1.62 mmol)] in THF (5 mL) was added to a cooled (−40° C.) and stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (200 mg, 0.54 mmol) in THF (10 mL). The reaction mixture was warmed to 0° C., for 1 h and then re-cooled to −40° C. MeI (766 mg, 5.35 mmol) was added and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched carefully with water (50 mL) and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex afforded 2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (184 mg, 88%) as a white solid: LCMS RT: 2.74 min, MH+: 380.3. This transformation can also be accomplished by using other amide bases such as LDA.
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4](O)=[N:5][CH:6]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:22])=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:4]1[C:3]2=[CH:8][CH:9]=[CH:10][N:2]2[N:1]=[CH:6][N:5]=1
Reactant: Oc1ncnn2cccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ncnn2cccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of pyrrolo[2,1-f][1,2,4]triazin-4-ol (3.70 g, 27.4 mmol, see generally, PCT Appi. WO 2000/071129 the disclosure of which is herein incorporated by reference in its entirety) in 40 mL of toluene at room temperature was added 4.77 mL (27.4 mmol) of diisopropylethylamine followed by 7.70 mL (82.6 mmol) of phosphorus oxychloride. The reaction mixture was heated at 100° C. for 18 h. After cooling to room temperature, the reaction was slowly added to a solution of 5% aq NaHCO3 solution (100 mL) at 0° C. Upon completion of the addition, the biphasic mixture was allowed to stir at room temperature for 30 min. The aqueous layer was extracted with EtOAc (3×100 mL) and the pooled organic extracts were washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude product (4.10 g, 97%) as a yellow solid. 1H NMR (CDCl3) δ 8.14 (s, 1H), 7.80 (dd, 1H, J=2.4, 1.5 Hz), 6.91 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:42][C@@H:43]([NH2:48])[C:44]([F:47])([F:46])[F:45]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17](=[O:19])[NH:48][C@H:43]([CH3:42])[C:44]([F:47])([F:46])[F:45])=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H](NC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1)C(F)(F)F
Yield: 68.3 %

Procedure:
Dissolve [4-(tert-butoxycarbonylamino-methyl)-phenyl]-acetic acid (190 mg, 0.63 mmol) in DCM (12.4 mL) and add triethylamine (354 μL, 2.5 mmol), DMAP (8 mg, 0.063 mmol), EDC (145 mg, 0.756 mmol), HOBt (102 mg, 0.756 mmol) and (R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (71 mg, 0.63 mmol) under nitrogen atmosphere. Stir the reaction overnight at room temperature. Concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:1 and 0:1) to obtain the desired intermediate (155 mg, 68%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:13][CH2:14][OH:15])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][CH2:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)(=[O:26])=[O:25]
Reactant: OCCOc1ccccc1OCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccccc1OCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
2-Cyclopropylmethyloxy-1-(2-hydroxyethyloxy)benzene (2.7 g, 13.0 mmol), prepared as in Example 1, Step (a), and triethylamine (2.7 mL, 19.5 mmol) were dissolved in methylene chloride (20 mL) and the solution was cooled in an ice bath. Methanesulfonyl chloride (1.2 mL, 15.5 mmol) in methylene chloride (10 mL) was added dropwise to the solution and the mixture was stirred at 0° C. for 30 minutes. Water was added and the mixture was stirred vigorously at room temperature for 15 minutes. The mixture was extracted into methylene chloride. The organic phase was separated, washed with 2N hydrochloric acid and then brine, and dried over magnesium sulfate. Evaporation gave 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate (3.7 g, 12.9 mmol) as a white solid, m.p. 90°-91° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:13]3[NH:12][C:11]([CH3:23])=[C:10]2[C:24]#[N:25])=[CH:5][CH:4]=1)#[N:2].ClCCl.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:13]3[N:12]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=3)[C:11]([CH3:23])=[C:10]2[C:24]#[N:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(-c3cccs3)nc2N1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(-c3cccs3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-(4-cyanophenyl)-5-methyl-2-thiophen-2-yl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (70 mg, 230 μmol) was stirred in abs. dichloromethane (60 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (131 mg, 690 μmol, 3 eq.), anhydrous copper(II) acetate (125 mg, 690 μmol, 3 eq.), abs. pyridine (1668 μl) and triethylamine (70 mg, 690 μmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (44 mg, 230 μmol, 1 eq.), anhydrous copper(II) acetate (42 mg, 230 μmol, 1 eq.) and abs. pyridine (500 μl) were then added, and the mixture was stirred at RT for a further 3 d. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and pyridine and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless solid (40.1 mg, 36% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[S:39](Cl)(=[O:41])=[O:40]>C1COCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[N:8]=1)[S:39]([C:32]1[CH:33]=[C:34]([F:38])[C:35]([F:37])=[CH:36][C:31]=1[F:30])(=[O:41])=[O:40]
Reactant: COc1ccc(CNc2ccnc(F)n2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccnc(F)n2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Yield: 63.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 15a by using the N-(2,4-dimethoxybenzyl)-2-fluoropyrimidin-4-amine (0.20 g, 0.76 mmol) prepared in Example 24a, LiHMDS (1.0 M in THF, 0.91 mL, 0.91 mmol), 2,4,5-trifluorobenzenesulfonyl chloride (0.19 g, 0.84 mmol) and THF (3.0 mL), to yield the title compound (0.22 g, 63%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14]C)=O)=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CO>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][N:4]=2)=[O:14])=[CH:19][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ncc2cccnc2c1O
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1ncc2cccnc2c1O

Procedure:
Methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate (10.0 grams, 48.9 mmol) prepared as described in Example 1 was dissolved/suspended in MeOH (100 mL) and treated with 4-fluorobenzylamine (6.1 g, 48.9 mmol). The reaction was brought to reflux and the MeOH allowed to evaporate until the total volume was approximately 30 mL. The reaction was refluxed for 5 hours more and a white solid precipitated. The reaction was cooled and the solid collected by filtration, washed with a minimum of MeOH and dried on the pump to give the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:17][C:18](=O)C>>[C:10]1([CH2:9][O:8][C:7]2[C:2]3[N:3]([CH:17]=[CH:18][N:1]=3)[N:4]=[CH:5][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)CCl
Reactant: Nc1nnccc1OCc1ccccc1
Product: c1ccc(COc2ccnn3ccnc23)cc1

Procedure:
For example, condensation of 3-amino-4-phenylmethoxypyridazine with chloroacetone gives an 8-phenylmethoxyimidazo[1,2-b]pyridazine with a methyl at the 2-position and a hydrogen as shown in the following reaction Scheme II: ##STR14##
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH:12](Br)Br)=[C:8]([Cl:15])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C[O:17]CCO>[N+]([O-])([O-])=O.[Ag+]>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH:12]=[O:17])=[C:8]([Cl:15])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(C(Br)Br)c1=O
Reactant: COCCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CC(C)(C)n1ncc(Cl)c(C=O)c1=O

Procedure:
Into 300 ml of a 2-methoxyethanol solution of 27.4 g of 2-tert-butyl-5-chloro-4-dibromomethylpyridazin-3-(2H)-one, 200 ml of an aqueous solution of 39 g of silver nitrate was dropwise added at 10° C. over a period of 10 minutes, and the mixture was reacted for one hour under heating and refluxing. After cooling, insoluble matters were filtered off, and 500 ml of benzene was added to the filtrate. The mixture was washed with water, and the extract layer was dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure to obtain 12.2 g of 2-tert-butyl-5-chloro-4-formylpyridazin-3-(2H)-one having a melting point of from 61° to 66° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([O-])([O-])=[O:15].[K+].[K+].C[C:21]([CH3:23])=[O:22]>>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][C:21]([O:15][CH3:14])=[O:22])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: [K+]
Product: COC(=O)CCc1ccc(OCC(=O)OC)cc1
Yield: 36 %

Procedure:
To a mixture of methyl 3(4-hydroxy phenyl)propionate (60 grams, 333 mmol), anhydrous K2CO3 (180 grams, 1.30 mol) in anhydrous acetone (1 liter) was added methyl chloro acetate (74.2 grams, 684 mmol) and refluxed for 40 hours. Acetone was distilled and water (1000 mL) was added. Crude 15 extracted into chloroform, distilled chloroform and high vacuum distilled to get pure 15 (30 grams, 36%) as a colorless low melting solid. Bp12 210-213° C. The structure was confirmed by NMR. IHNMR (CDCl3) δ 2.58 (t, 2H, CH2), 2.90(t, 2H, CH2), 3.62(s, 3H, ester), 3.80(s, 3H, ester), 4.60(s, 3H, OCH2), 6.80(d, 2H, Ar), 7.12(d, 2H, Ar).
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]([CH:28]=[O:29])[CH3:27].[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48]([O:49][CH:50]4[CH2:55]CNC[CH2:51]4)=[C:43]3[CH:42]=[N:41]2)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>C(N(CC)CC)C>[C:43]([C:10]1[N:15]=[CH:14][C:13]([C:28]([N:26]2[CH2:27][CH2:55][CH:50]([O:49][C:48]3[N:47]=[CH:46][N:45]=[C:44]4[N:40]([C:37]5[CH:36]=[CH:35][C:34]([S:31]([CH3:30])(=[O:32])=[O:33])=[CH:39][CH:38]=5)[N:41]=[CH:42][C:43]=34)[CH2:51][CH2:25]2)=[O:29])=[CH:12][CH:11]=1)([CH3:44])([CH3:48])[CH3:42]
Reactant: CN(C)C=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 20 mL reaction vial was placed a stir bar, 4-t-butylnictinic acid (30 mg), 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg) and DMF (1 mL). The mixture was stirred 10 min at room temperature under N2. 1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (17.2 mg) and triethylamine (100 μl) was added. After stirred 3 hours at room temperature under N2, the reaction mixture was filtered through a syringe filter. The filtrate was concentrated and purified by HPLC. 1H NMR (DMSO-d6, 400 MHz) δ 1.34 (s, 9H), 1.88 (m, 2H), 2.14 (m, 2H), 3.28 (s, 3H), 3.62 (m, 3H), 4.06 (m, 1H), 5.72 (m, 1H), 7.53 (d, 1H), 7.84 (m, 1H), 8.15 (d, 2H), 8.18 (m, 1H), 8.55 (d, 2H), 8.60 (m, 1H), 8.66 (s, 1H), 8.81 (s, 1H). Exact mass calculated for C27H30N6O4S 534.20, found 535.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[BH4-].[Na+]>O>[OH:17][CH:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:12]=2[CH:11]=[CH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]1=2
Reactant: Cc1cccc2c(=O)c3ccccc3ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1C=Cc1ccccc1C2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
26 g. of 1-Methyl-5H-dibenzo[a,d]cyclohepten-5-one are dissolved in 200 ml. of dioxane, a solution of 9 g. of sodium borohydride in 35 ml. of water is added thereto and the mixture is stirred at room temperature for 4 hours. The mixture is subsequently evaporated under reduced pressure. The residue is shaken with ether and water. The ethereal phase is washed with water, dried over sodium sulfate, filtered and evaporated. The 5-hydroxy-1-methyl-5H-dibenzo[a,d]cycloheptene obtained is recrystallized from petroleum ether and melts at 114°-116° C.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][NH2:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][I:15].[C:16](=[S:18])=[S:17]>>[IH:15].[CH3:14][S:17][C:16](=[S:18])[NH:13][CH2:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: CI
Reactant: NCCCNC(=O)c1ccccc1
Product: CSC(=S)NCCCNC(=O)c1ccccc1
Product: I

Procedure:
(i) 3-Benzoylaminopropylamine was treated successively with carbon disulphide and methyl iodide according to the general procedure of Example 1(a)(b) to give S-methyl-N-(3-benzoylaminopropyl)dithiocarbamate hydriodide
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].P(Cl)(Cl)(Cl)=O.O.O.Cl[Sn]Cl.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[C:28](=[O:30])[CH:27]=[CH:26][C:25]2=O.Cl>C(#N)C>[CH2:1]([O:7][C:25]1[C:24]2[C:29](=[C:20]([O:19][CH3:18])[CH:21]=[CH:22][CH:23]=2)[C:28]([OH:30])=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: COc1cccc2c1C(=O)C=CC2=O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CCCCCCOc1ccc(O)c2c(OC)cccc12

Procedure:
10 ml of hexyl alcohol and 50 ml of acetonitrile were placed in a 1 l three-necked flask, and 12.8 g of phosphorus oxychloride was dropwisely added thereto under cooling with ice while stirring. Thereafter, 9.5 g of SnCl2.2H2O was added to the reaction mixture at room temperature. Then, 7.5 g of 8-methoxy-1,4-naphthoquinone was added to the reaction mixture at room temperature. The reaction mixture was refluxed for 2 hours on steam bath. The reaction mixture was poured into 1.2 l of diluted hydrochloric acid and extracted with 500 ml of ethyl acetate. The ethyl acetate solution was washed with water, dried with MgSO4 overnight, and concentrated under reduced pressure to obtain 9 g of oily substance. The oily substance was purified by column chromatography using a mixed solvent of n-hexane and ethyl acetate and, then, recrystallized from benzene to obtain 6 g of white crystals having a melting point of 105° to 107° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[N:12]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:13](=[O:16])[CH2:14]Cl.[C:23]([O-:26])(=[O:25])[CH3:24].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[N:12]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:13](=[O:16])[CH2:14][O:26][C:23](=[O:25])[CH3:24]
Reactant: Cc1ccc2ccccc2c1N(C(=O)CCl)C1CCOC1=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)N(c1c(C)ccc2ccccc12)C1CCOC1=O
Temperature: 25 °C

Procedure:
A mixture of 18.2 g of N-(2-methylnaphthyl)-N-(2-oxo-tetrahydrofuran-3-yl)-N-chloroacetyl-amine, 11.5 g of anhydrous sodium acetate and 0.1 g of KJ in 70 ml of dimethylformamide (DMF) is heated at 110° for 16 hours. The reaction mixture is afterwards cooled to room temperature, poured into 200 ml of water and extracted three times with 50 ml of ethyl acetate each time. The combined extracts are washed with 50 ml of water, dried over sodium sulfate, filtered and then concentrated by evaporation. The dark-brown oil remaining is purified through silica gel 60 (particle size 0.06-0.2 mm) using chloroform/diethyl ether (1:1) as the eluant. The last 10 of 12 fractions are combined and the eluant is evaporated off. The diastereoisomeric mixture of the compound No. 19 which remains solidifies on cooling, m.p. 50°-70°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:15]>CN(C)C=O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][NH:1][C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])=[CH:4][C:5]=1[F:13]
Reactant: COC(=O)c1ccc(CN)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)n2ccnc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.5 %

Procedure:
To a mixture of methyl 4-(aminomethyl)-2-fluorobenzoate (106.9 mg, 0.584 mmol) in N,N-dimethyl formamide (4.0 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 98.9 mg, 0.592 mmol). After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 2-Fluoro-4-{[(imidazole-1-carbonyl)-amino]-methyl}-benzoic acid methyl ester (187.0 mg) which was used without further purification.