Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[I:19]I>C(Cl)(Cl)Cl.C(#N)C.FC(F)(F)C([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:19]
Reactant: II
Reactant: CC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 106.8 %

Procedure:
Acetic acid (5R)-3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (15.2 g, 60 mM) was dissolved in a mixture of chloroform (100 ml) and acetonitrile (100 ml) under nitrogen, and silver trifluoroacetate (16.96 g, 77 mM) added. Iodine (18.07 g, 71 mM) was added in portions over 30 minutes to the vigorously stirred solution, and stirring continued at ambient temperature for 18 hours. As reaction was not complete, a further portion of silver trifluoroacetate (2.64 g, 12 mM) was added and stirring continued for 18 hours. After filtration, the mixture was added to sodium thiosulfate solution (3%, 200 ml) and dichloromethane (200 ml), and the organic phase separated, washed with sodium thiosulfate (200 ml), saturated aqueous sodium bicarbonate (200 ml), brine (200 ml), dried (magnesium sulfate), filtered and evaporated. The crude product was suspended in isohexane (100 ml), and sufficient diethyl ether added to dissolve out the brown impurity while stirring for 1 hour. Filtration gave the desired product (24.3 g) as a cream solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>C(#N)C>[CH2:34]([NH:36][C:37]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:16]=1)=[O:38])[CH3:35]
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCNC(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.1 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.45 g, 1.1 mmol), potassium carbonate (0.47 g, 3.4 mmol) and acetonitrile (26 ml) was stirred at room temperature for 20 minutes. Successively ethyl isocyanate (0.36 g, 5.1 mmol) was added to the mixture, and the mixture was refluxed for 3 hrs. After cooling, the precipitates were collected by filtration, dissolved in chloroform and subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (15:1, v/v) were collected, concentrated and recrystallized from chloroform-hexane to give the titled compound (0.25 g, 63%) as white crystals.
Reaction SMILES: COC[O:4][CH:5]([CH2:25][N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][C:27]1=[O:38])[CH2:6][NH:7][CH:8]1[CH2:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[C:10](=[O:24])[CH2:9]1.Cl>CO.O1CCCC1>[OH:4][CH:5]([CH2:25][N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][C:27]1=[O:38])[CH2:6][NH:7][CH:8]1[CH2:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[C:10](=[O:24])[CH2:9]1
Reactant: COCOC(CNC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1)Cn1c(=O)cnc2ccc(OC)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc(=O)n(CC(O)CNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 61.6 %

Procedure:
6-(4-{[2-(Methoxymethoxy)-3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]amino}-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (115 mg, 0.220 mmol) was dissolved in a mixed solvent of methanol/tetrahydrofuran (1:1,2 ml). To this solution was added 4N hydrochloric acid aqueous solution (1 ml) under cooling on ice and the mixture was stirred at 60° C. for 7 hours. The reaction solution was cooled in the air, and the solvent was then removed under reduced pressure. To the residue was added 1N aqueous sodium hydroxide solution under cooling on ice to neutralize the residue which was then extracted using a lower layer solvent of chloroform/methanol/water (7:3:1). The extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 65 mg (61%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:19]([O:29]COC)=[C:18]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:19]([OH:29])=[C:18]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[CH:17]=2)=[O:40])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCOc1c(-c2cccc(C)c2)cc(C(=O)NCCCCCCCc2ccccc2)cc1-c1cccc(C)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2O)c1
Yield: 76.5 %

Procedure:
To a solution of N-7-phenylheptyl-3,5-bis-(3-methylphenyl)-4-methoxymethoxybenzamide (1.04 g, 1.94 mmol) in 3.5 mL THF was added 2N HCl (1.1 mL, 2.2 mmol) at room temperature and the reaction mixture was refluxed for 2 hours before a catalytic amount of camphorsulfonic acid was added. The reaction was refluxed overnight and the resulting goo was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. This yielded an oil that was passed through a pad of silica gel using 20% EtOAc: 80% Hexanes. There yielded 730 mg, 81% of a light yellow viscous oil. 1H NMR (CDCl3) δ 1.33–1.39 (m, 6H); 1.59–1.63 (m, 6H); 2.42 (s, 6H); 2.58 (t, J=7.69 Hz, 2H); 3.44 (quartet, J=7.03 Hz, 2H); 6.06 (t, J=7.50 Hz, 1H); 7.14–7.18 (m, 3H); 7.22–7.28 (m, 4H); 7.34–7.40 (m, 6H); 7.68 (s, 2H); IR 3525, 3025, 2925, 2850, 1630, 1600, 1530, 1460, 1325, 1230, and 700 cm−1; mass spectrum [(+)ESI], m/z 492 [M+H]+; Anal Calcd. For C34H37NO2: C, 83.06; H, 7.59; N, 2.85. Found: C, 83.80; H, 7.62; N, 2.93.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>O.[Pt]=O.C(O)C>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccccc1OCC(F)(F)F
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80147.1 %

Procedure:
A mixture of 1-(2,2,2-trifluoroethoxy)-2-nitrobenzene (15 g, 68 mmol), platinum oxide hydrate (100 mg) and absolute ethanol (80 mL) was hydrogenated 18 hours with stirring at 25° C. and 15 psi of pressure. The reaction mixture then was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to give 2-(2,2,2-trifluoroethoxy)aniline (10.4 g, 54.5 mol), m.p. 49°-50° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[CH2:16]1
Reactant: CC(C)C(O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(O)C1CNC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.8 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-(1-hydroxy-2-methylpropyl)azetidine-1-carboxylic acid tert-butyl ester (0.84 g, 3.66 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 40 min. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The solvents were reduced in vacuo to afford 1-Azetidin-3-yl-2-methylpropan-1-ol as a white solid (0.42 g, 88%). 1H NMR (400 MHz, CDCl3): δ 3.63-3.62 (3 H, m), 3.53-3.51 (2 H, m), 2.88-2.87 (1 H, m), 1.62-1.62 (1 H, m), 0.89 (6 H, dd, J=6.84, 4.72 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[C:16]#[N:17])[C:10]2[CH:33]=[C:34]([CH2:41][CH3:42])[C:35]([C:37]([F:40])([F:39])[F:38])=[CH:36][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:43]([Sn](CCCC)(CCCC)CCCC)=[N+:44]=[N-:45]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:18][C:19]2[CH:20]=[C:21]([C:29]([F:31])([F:32])[F:30])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=2)[C:16]2[N:43]=[N:44][NH:45][N:17]=2)[C:10]2[CH:33]=[C:34]([CH2:41][CH3:42])[C:35]([C:37]([F:40])([F:38])[F:39])=[CH:36][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Yield: 79.1 %

Procedure:
Heat a mixture of (S)-5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid tert-butyl ester (0.510 g, 0.837 mmol), azidotributyltin (0.344 mL, 1.26 mmol) in anhydrous toluene (20 mL) at 100° C. under nitrogen for 16 h. Dilute the cooled mixture with ethyl acetate (50 mL) and wash with aqueous NaF (50 mL) and brine (50 mL). Dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-60%), to provide the title compound (0.432 g, 79%), MS (ES+): 653 (M+H).
Reaction SMILES: [Na].[F:2][C:3]1[C:4]([CH3:18])=[C:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1.C([O:21][CH:22]=[C:23]([C:29](OCC)=O)[C:24]([O:26]CC)=[O:25])C.O.C(=O)(O)[O-].[Na+]>C(#N)C>[F:2][C:3]1[C:4]([CH3:18])=[C:5]([N:9]2[C:22](=[O:21])[C:23]([C:24]([OH:26])=[O:25])=[CH:29][N:11]=[C:10]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1c(F)cccc1NC(=N)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: Cc1c(F)cccc1-n1c(-c2ccccc2)ncc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(3-fluoro-2-methylphenyl)benzenecarboximidamide sodium salt (1:1) (i.e. the product from Example 5, Step A) (51.0 g, 200 mmol) in acetonitrile (300 mL) was added diethyl ethoxymethylenemalonate (44.04 g, 200 mmol). The reaction was stirred at room temperature for 30 min followed by the addition of water (3.6 mL, 200 mmol). The reaction was then stirred for another 30 min Water (100 mL) was added to the residue, followed by a saturated solution of sodium bicarbonate (300 mL), and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid until the pH was 1-2, and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure to provide a solid, which was washed with diethyl ether and dried under reduced pressure to afford the title product as a off-white solid (18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:7])=O.FS(OC)(=O)=O.C(Cl)Cl.[NH3:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:23])=[NH:7]
Reactant: N
Reactant: COc1cccc(OC)c1C(N)=O
Agent: COS(=O)(=O)F
Solvent: CCO
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=N)N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2,6-dimethoxybenzamide (68 g.; prepared as described by P. Grammaticakis, Compt. rend., 1968, 267C,152), methyl fluorosulphonate (45 g.) and anhydrous methylene dichloride (1 l.) was stirred at room temperature for 3 hours. The solution was evaporated in vacuo, and the residue treated with anhydrous diethyl ether to give crude methyl 2,6-dimethoxybenzimidate fluorosulphonate as a white solid, m.p. 115°-137° C. This was dissolved in anhydrous ethanol (1 l.) and the solution was cooled to 0° C. Anhydrous ethanolic ammonia (350 ml.; prepared by saturation of anhydrous ethanol with anhydrous ammonia at 0° C.) was added, and the mixture kept at room temperature for 4 days. The solution was filtered, the filtrate was evaporated in vacuo, the residue was treated with an excess of 2N sodium hydroxide solution, and the precipitated solid was filtered off, washed with water and recrystallised from isopropanol to give 2,6-dimethoxybenzamidine (15 g.), m.p. 170°-174° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:19]O>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc2cccnc2c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc2cccnc2c1

Procedure:
To a solution of example 11A (1.98 g, 10.59 mmol) in 40 mL of anhydrous methanol was slowly added SOCl2 (1.5 mL, 31.7 mmol), and a drop of dimethylformamide as catalyst. The mixture was refluxed for 5 hrs and then concentrated under reduced pressure. The residue was dissolved in water (10 mL) and neutralized with aqueous sodium bicarbonate to pH 8. The product was extracted with methylene chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure to afford 2.13 g of the title compound. MS (ESI+) m/z 202 (M+H)+.
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.C(N(CC)CC)C.[C:21]([C:23]1[C@@H:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[N:27]2[N:37]=[C:38]([NH:40][C:41](=[O:50])OCC3C=CC=CC=3)[N:39]=[C:26]2[N:25]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)[C:24]=1[CH3:61])#[N:22].[NH2:62][CH2:63][CH2:64][OH:65]>CN(C1C=CN=CC=1)C.ClCCl>[C:21]([C:23]1[C@@H:28]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][CH:34]=2)[N:27]2[N:37]=[C:38]([NH:40][C:41]([NH:62][CH2:63][CH2:64][OH:65])=[O:50])[N:39]=[C:26]2[N:25]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:58])([F:60])[F:59])[CH:52]=2)[C:24]=1[CH3:61])#[N:22]
Reactant: NCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)NCCO)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 4 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas and at 0° C., 4-nitrophenyl chloroformate (7.3 mg, 36 μmol, 2 eq.), triethylamine (3.1 mg, 40 μmol, 2.2 eq.) and DMAP (0.2 mg, 1.8 μmol, 0.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (10 mg, 18 μmol) in dry dichloromethane (1 ml), and the mixture was stirred at 4° C. for 12 h. At 0° C., 2-aminoethanol (8.5 mg, 139 μmol, 10 eq.) was then added, and the mixture was once more stirred at 4° C. for 12 h. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (1.9 mg, 27% of theory).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[C:17](#[N:19])[CH3:18]>>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:10]=1)[CH2:18][C:17]#[N:19]
Reactant: O=Cc1cccc(OCC2CCCCO2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCC2CCCCO2)c1

Procedure:
Addition of acetonitrile to 3-((tetrahydro-2H-pyran-2-yl)methoxy)benzaldehyde gave 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propanenitrile as a yellow oil. Yield (1.1 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.26-7.31 (m, 1H), 6.93-6.99 (m, 2H), 6.87-6.92 (m, 1H), 4.97-5.03 (m, 1H), 3.68-4.01 (m, 4H), 3.47-3.55 (m, 1H), 2.75 (d, J=6.4, 2H), 1.90-1.93 (m, 1H), 1.43-1.71 (m, 5H).
Reaction SMILES: [O:1]=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[OH:1][C:2]([CH2:14][C:13]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(=O)c1ccncc1
Product: CCOC(=O)C(O)(CC(=O)c1ccncc1)C(=O)OCC

Procedure:
Diethyl ketomalonate (17.4 g, 0.1 mol) was heated with 4-acetylpyridine (12.1 g, 0.1 mol) at 120° C. for 15 h under nitrogen to provide diethyl 2-hydroxy-2-(4-pyridyl)cabonylmethyl-malonate as a crystalline solid. The diester was refluxed in ethanol with a slight excess of hydrazine hydrate hydrochloride for 15 h to provide 3-hydroxy-6-(4-pyridyl)-4-carbethoxy-pyridazine (4, Scheme 1). The above ester was recrystallized from ethanol, hydrolyzed with aqueous sodium hydroxide followed by careful neutralization with hydrochloric acid to afford 3-hydroxy-6-(4-pyridyl)-pyridazine-4-carboxylic acid (5, Scheme 1). The acid was dissolved in phosphorous oxychloride containing a catalytic amount of DMF and the mixture was allowed to react at 80° C. for 4 h to provide 3-chloro-4-chlorocarbonyl-6-(4-pyridyl)pyridazine (6, Scheme 1) as a dark oil The above dichloride was treated with gaseous ammonia in acetonitrile to afford the title compound as a tan solid. The above dichloride was treated with excess gaseous ammonia to afford the title compound as a tan solid: 1H NMR (DMSO-d6) δ 8.80 (d, J=6 Hz, 2H), 8.59 (s, 1H), 8.20 (s, 1H), 8.17 (d, 6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:23])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:21]([NH:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)([CH3:23])[CH3:20]
Reactant: CN1CCN(C(=O)c2nc3c(N)cccc3[nH]2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Nc1cccc2[nH]c(C(=O)N3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (4-amino-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 43; 50 mg, 0.19 mmol) in dichloroethane (10 mL), was added acetone (0.07 mL, 0.96 mmol) and acetic acid (10 drops), followed by NaBH(OAc)3 (203 mg, 0.96 mmol). The reaction mixture was stirred at room temperature for 16 h, and then was quenched with satd aq NaHCO3 (5 mL). The aqueous layer was extracted with CHCl3 (10 mL), and the combined organic layers were dried (Na2SO4) and then concentrated under reduced pressure. The crude product was purified on silica gel (10 g; 0-10% methanol (2 M NH3)/CH2Cl2) to give 35 mg of the title compound (60%). MS (ESI): mass calculated for C16H23N5O, 301.39; m/z found, 302.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.11-11.07 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.37 (d, J=7.8 Hz, 1H), 4.80-4.65 (m, 2H), 3.92-3.78 (m, 2H), 2.56-2.53 (m, 4H), 2.36 (s, 3H), 1.85-1.81, (m, 1H), 1.32 (d, J=6.3 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=[O:15])[CH2:7][CH2:6]2.[CH:16](I)([CH3:18])[CH3:17].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:7][CH2:6]2
Reactant: CC(C)I
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)C(C(C)C)C(=O)CC2
Reaction time: 0.5 h

Procedure:
22.0 g of 3,4-dihydro-6,7-dimethoxy-2(1H)-naphthalenone were dissolved in 300 ml of dimethylformamide and treated with 13 g of potassium tert.-butylate. The solution was stirred at 18° for 30 minutes. After the addition of 19.7 g of isopropyl iodide the mixture was stirred for a further 30 minutes, whereby the temperature was held below 30°, and then poured into water. The product was extracted with ether, the extract was washed with water, dried over magnesium sulfate and evaporated. The oil which remained behind was purified by column chromatography (silica gel, hexane/ethyl acetate 6:1). There was obtained 3,4-dihydro-6,7-dimethoxy-1-isopropyl-2(1H)-naphthalenone, m.p. 77°-79°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([S:11](Cl)(=[O:13])=[O:12])=[CH:5][C:4]=1[C:15]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[CH:23]=1.ClS(O)(=O)=O.[CH3:29][NH:30][CH3:31]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([S:11]([N:30]([CH3:31])[CH3:29])(=[O:13])=[O:12])=[CH:5][C:4]=1[C:15]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[CH:23]=1
Reactant: CNC
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1-c1cn2cccnc2n1
Agent: O=S(=O)(O)Cl
Product: COc1cc(OC)c(S(=O)(=O)N(C)C)cc1-c1cn2cccnc2n1

Procedure:
Prepared from 2-(2,4-dimethoxy-5-chlorosulphonyl-phenyl)-imidazo[1,2-a]pyrimidine (prepared from 2-(2,4-dimethoxyphenyl[1,2-a]pyrimidine and chlorosulphonic acid) and 40% dimethylamine analogously to Example 25.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N:23]1([CH2:22][CH2:21][CH2:20][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCCN1CCCCC1
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCCN1CCCCC1

Procedure:
Salicylaldehyde (27 g) is treated first with 11 g of 50% sodium hydride in 175 ml of dimethylformamide and then with 150 ml of a 2 N toluene solution of N-(3-chloropropyl)-piperidine following the procedure described in Example 31A, yielding 47.7 g of the title compound as an oil, boiling point 155°-160° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:10]=[C:9]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[NH2:6][C:5]1[C:4]([CH3:3])=[CH:10][C:9]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:8][C:7]=1[I:1]
Reactant: Cc1cc(-n2cnnn2)ccc1N
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-n2cnnn2)cc(I)c1N

Procedure:
A solution of iodine monochloride (4.46 g) in acetic acid (30 cm3) was added dropwise to a stirred solution of 2-methyl-4-(tetrazol-1-yl)aniline (4 g) in acetic acid (30 cm3). After 2 hours the mixture was brought to pH 6 by addition of aqueous sodium carbonate solution and extracted with dichloromethane (250 cm3). The organic phase was dried (MgSO4), filtered and evaporated to yield a dark brown solid. This solid was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane to afford 1-(4-amino-3-iodo-5-methylphenyl)tetrazole, m.p. 172°-175°, (6.2 g).