Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH2:19][O-:20].[Na+]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:20][CH2:19][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[O-]
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [Na+]
Product: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
5 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile in 60 ml of absolute alcohol are heated to reflux temperature for 1 hour in the presence of 30 mg of sodium ethylate. After distilling off the alcohol the residue is treated with water and the mixture is extracted three times with methylene chloride. The combined extracts are washed with water, dried over anhydrous sodium sulphate and evaporated, and the residue is distilled in a bulb-tube oven at 230°-250° C./0.1 mmHg. There is obtained ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a clear resin which becomes solid; m.p. 68°-71° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:1][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN(Cc2ccccc2)CCO1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NCC1CN(Cc2ccccc2)CCO1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-azidomethyl-4-benzylmorpholine (15 g) in toluene (40 ml) is added dropwise to a stirred solution of 70% sodium bis(2-methoxyethoxy)aluminum hydride in toluene (60 ml) cooled to -5° C. The reaction mixture is stirred at 25° C. for 1.5 hours and cooled to 10° C., and the excess of the reducing agent is decomposed by the cautious addition of 10% aqueous sodium hydroxide solution. The organic layer is separated, washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the title compound is obtained a an oil (11 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[CH:5][CH:4]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=1.[OH-].[K+].Cl>O>[CH3:32][N:31]([CH3:33])[C:27]1[CH:26]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:30]=[CH:29][C:28]=1[CH:9]([C:18]1[CH:17]=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[CH:14][C:13]=1[C:11]([OH:10])=[O:12])[C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:22])[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2C(=O)O)c2ccc(N(C)C)cc2N(C)C)cc1
Temperature: 25 °C

Procedure:
A mixture of 6.0 g of 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide prepared as described in part A above, 100 ml of water, 3.5 g of N,N,N',N'-tetramethyl-m-phenylenediamine and 1.8 g of flake potassium hydroxide was heated at reflux with stirring for a period of approximately eighteen hours and then allowed to cool to room temperature. The resultant solution was made slightly acidic by the addition of ten percent aqueous hydrochloric acid causing a cream-colored solid to precipitate. The solid was collected by filtration, washed with water and air dried at 40° C. to obtain 2-[2,4,4'-tris(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid (Formula III: R=CH3 ; X=H; Y=4-(CH3)2NC6H4 ; Z=2,4-[(CH3)2N]2C6H3) as a slightly sticky, cream-colored solid melting over the range 119°-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[O:10][CH:11]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH3:12])([O-])=O>C(O)C.[C].[Pd]>[NH:17]1[C:13]([CH:11]([O:10][C:9]2[CH:8]=[C:7]([CH:20]=[CH:19][CH:18]=2)[O:6][C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[NH2:1])[CH3:12])=[N:14][N:15]=[N:16]1
Reactant: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)c1nnn[nH]1
Agent: [Pd]
Solvent: CCO
Product: CC(Oc1cccc(Oc2ccccc2N)c1)c1nnn[nH]1

Procedure:
In 30 ml of ethanol was dissolved 5-[1-[3-(2-nitrophenoxy)phenoxy]ethyl]-1H-tetrazole and catalytic hydrogenation was carried out in the presence of 0.3 g of palladium-carbon at atmospheric temperature and pressure. After the reaction, the catalyst was filtered off and the filtrate was concentrated to give 2.1 g of the title compound as a brown oil.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=S)[NH2:21]>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([NH:2][NH2:3])=[NH:21]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(N)=S)c1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=N)NN)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Hydrazine hydrate (430 μl) is added dropwise to a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzene thioamide (1.71 g, 5.48 mmol) in 30 ml of methanol. The solution is stirred at room temperature under nitrogen for five hours, then concentrated in vacuo to half its original volume. This material is chromatographed, eluting with ethyl acetate:hexane (gradient of 1:1 to 3:1) to give 1.15 g (68%) of a glassy pale yellow solid. This material darkens and softens after two days at room temperature.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: NCC(O)c1ccccc1Cl
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccccc2Cl)cc1
Yield: 73.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(2-chlorophenyl)ethanol (prepared as described in Preparation 11), 3.11 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.3 g of sodium cyanoborohydride, 3.25 g of the title compound were obtained having an Rf=0.39 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][C@H:16]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[C:17](O)=[O:18])=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:3]1.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[CH3:37][N:38]1[CH2:39][CH2:40][CH:41]([N:44]2[CH2:49][CH2:48][N:47]([C:17](=[O:18])[C@H:16]([NH:15][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([N:6]4[C:2](=[O:1])[NH:3][C:4]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[N:5]4)[CH2:8][CH2:9]3)=[O:14])[CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH2:46][CH2:45]2)[CH2:42][CH2:43]1
Reactant: O=C(O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1
Reactant: CN1CCC(N2CCNCC2)CC1
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccc4c(c3)CCCC4)NC(=O)N3CCC(n4nc(-c5ccccc5)[nH]c4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 54c) from 300 mg (0.61 mmol) (R)-2-{[4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionic acid and 120 mg (0.66 mmol) 1-(1-methyl-piperidin-4-yl)-piperazine.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[N:28]=[C:29]=[O:30])([CH3:18])[CH3:17]>C(OCC)(=O)C>[CH3:18][CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29]([NH:9][O:8][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:30])[CH3:17]
Reactant: NOC(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of 1,1-diphenylmethoxyamine (0.9 g, 0.0045 mol) (E. L. Schumann, et al, Journal of Medicinal Chemistry, Volume 7, pages 329-334 (1964)) in 20 ml of ethyl acetate is added 2,6-diisopropylphenyl isocyanate (0.91 g, 0.0045 mol) and the reaction mixture is stirred for 20 hours at room temperature. The volatiles are removed under reduced pressure and the residue treated with 30 ml hexane-ethyl acetate (4:1). The precipitated solid is filtered and dried affording 1.45 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(diphenylmethoxy)-urea; mp 152°-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][O:8][C:9]([C:11]#[C:12][C:13]([O:15][CH3:16])=[O:14])=[O:10]>CO>[S:4]1[CH:5]=[CH:6][C:2]([NH:1][C:11](=[CH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([O:8][CH3:7])=[O:10])=[CH:3]1
Reactant: Nc1ccsc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)C=C(Nc1ccsc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Aminothiophene is redissolved in methanol (500 mL) cooled in an ice bath and dimethylacetylenedicarboxylate (80 g; 0.50 mol) is added dropwise. The mixture is stirred at room temperature for 15 hours and 30 minutes, the methanol removed under reduced pressure and 1,2-dichloroethane is added. This solvent is also evaporated off to give dimethyl 3-thienylaminobutenedioate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([NH2:27])=[O:22])=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) in DMF (2 mL) was added 1,1′-carbonyldiimidazole (39 mg, 0.24 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (308 L, 2.0 mmol) and stirred for 2 h at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:1 to 0:1) afforded the title compound (33 mg, 48%) as a white solid after trituration from dichloromethane. MS: m/e=345.2 [M+H]+.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12])=O)(C)(C)C>O1CCOCC1>[ClH:40].[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCN(c3cccc(Cl)c3)CC2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)N2CCN(c3cccc(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (8 mL) was added to a solution of 1-[trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-prolyl]-4-(3-chlorophenyl)piperazine (A, 260 mg) in 1,4-dioxane (8 mL) at room temperature. After stirring at room temperature for 20 min, the reaction mixture was evaporated in vacuo. The residue was washed with ether to give the titled compound (130 mg) as a white powder: 1H NMR (400 MHz, D2O) δ 2.32 (m, 1H), 2.49 (m, 1H), 3.24-3.36 (m, 5H), 3.62-3.74 (m, 5H), 3.71 (s, 2H), 4.45 (t, J=5.86 Hz, 1H), 4.92 (t, J=8.0 Hz, 1H), 7.03 (dd, J=2.0, 8.0 Hz, 1H), 7.05 (dd, J=2.0, 8.0 Hz, 7.15 (t, J=2.0 Hz, 1H), and 7.27 (t, J=8.0 Hz, 1H); mass spectrum (EI+) m/e 365 (M); IR (KBr) 3381, 3184, 3059, 2952, 1685, 1655, 1593, 1564, 1485, 1452, 1387, 1234, 935, 777, and 685 cm−1; Anal. Calcd for C17H24ClN5O2.2 HCl.1.5 H2O: C, 43.84; H, 6.28; N, 15.03; Cl, 22.83. Found: C, 43.65; H, 6.25; N, 14.59; Cl, 22.86.
Reaction SMILES: C([Mg]Br)C.C(Br)C.[Mg].CN([Mg]Br)C1C=CC=CC=1.[C:19]([C@H:22]1[C@@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][C:23]1([CH3:30])[CH3:29])(=O)[CH3:20].[CH:31](=[O:33])[CH3:32].Cl>C1C=CC=CC=1>[CH3:29][C:23]1([CH3:30])[CH2:24][CH2:25][CH2:26][C@H:27]([CH3:28])[C@@H:22]1[CH2:19][CH2:20][CH:31]([OH:33])[CH3:32]
Reactant: CC(=O)[C@H]1[C@@H](C)CCCC1(C)C
Reactant: CC=O
Agent: CC[Mg]Br
Agent: CN([Mg]Br)c1ccccc1
Agent: Cl
Solvent: CCBr
Solvent: c1ccccc1
Product: CC(O)CC[C@H]1[C@@H](C)CCCC1(C)C
Reaction time: 0.5 h

Procedure:
To 750 ml of an etheral solution of ethylmagnesium bromide (prepared from 302 g (2.7 moles) of ethyl bromide and 58,7 g (2.4 moles) magnesium turnings in 550 ml of ether) is added with cooling and stirring a solution of 238 g (2.2 moles) of freshly distilled dry N-methylaniline in 700 ml of dry benzene (N2 atmosphere). To the above freshly prepared solution of N-methylanilinomagnesium bromide is added during 25- 30 minutes a solution of 370 g (2.2 moles) of 1-acetyl-2,2,6-trimethyl cyclohexane (VI) in 370 ml of dry benzene while keeping the temperature at 15°C. After the addition of the ketone, the solution is allowed to stand for 30 minutes. A solution of 145.5 g (3.3 moles) of freshly distilled acetaldehyde in 150 ml of dry benzene is then added during 45 minutes, keeping the temperature at -13° to -10°C. After the addition of the aldehyde, the solution is allowed to stand for 90 minutes at the same temperature. 2000 ml of 3N hydrochloric acid is then added with stirring and cooling. The organic layer is separated and washed 6 times with 1000 ml 3N hydrochloric acid (to remove the N-methylaniline) and finally with 500 ml of water, 500 ml of sodium bicarbonate solution, and then water. The combined organic layers are dried over, anhydrous sodium sulfate and the solvents are removed by distillation at reduced pressure. The residue is distilled through a short Vigreux column. The product, cis-1-(2,2,6-trimethylcyclohexyl)-3-butanolone-1 (containing about 10% of the trans isomer) is collected at 98°-104°C/1 mm; yield 320 g (70%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[Cl:18])[N:9]=[CH:8][C:7]=1[C:19]#[N:20].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[Cl:18])[N:9]=[CH:8][C:7]=1[C:19]#[N:20])(=[O:3])[CH3:2]
Reactant: Cc1ccc(-n2ncc(C#N)c2N)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1c(C#N)cnn1-c1ccc(C)cc1Cl

Procedure:
Acetyl chloride (34 ml) was added to a stirred suspension of 5-amino-1-(2-chloro-4-methylphenyl)-4-cyanopyrazole (8.0 g) in chloroform (34 ml) at 0° C. A solution of pyridine (5.4 ml) in chloroform (34 ml) was then added to the suspension thus obtained over 10 minutes, with stirring at 0° C. to 2° C. maintained by external cooling. The reaction mixture was then stirred at laboratory temperature for 2.5 hours and the solution thus obtained was evaporated to dryness. The residue was dissolved in ethanol (100 ml) and basified with aqueous ammonia (d: 0.880). The basified solution was heated at reflux for 10 minutes and then evaporated to dryness. The residue was dissolved in dichloromethane (500 ml) and water (500 ml) and the organic layer was separated, washed successively once with water, twice with 2N hydrochloric acid and twice with water, dried over anhydrous magnesium sulphate and evaporated. The colourless solid thus obtained was crystallised from toluene (30 ml) to give 5-acetamido-1-(2-chloro-4-methylphenyl)-4-cyanopyrazole (6.54 g), m.p. 146°-147° C., in the form of colourless crystals.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([CH2:20][C:21](O)=[O:22])#[N:19].C1(N=C=NC2CCCCC2)CCCCC1.CCCCCC>ClCCl.C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:18]([CH2:20][C:21]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:22])#[N:19]
Reactant: N#CCC(=O)O
Reactant: CCCCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC(=O)CC#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The esterification reaction of hexadecanol was carried out under an inert atmosphere (Argon). To a solution of cyanoacetic acid (7.4853 g) and of hexadecanol (10.6674 g) in 50 ml of anhydrous dichloromethane and 5 ml of ethyl acetate, 50 ml of anhydrous dichloromethane containing 9.9864 g of dicyclohexylcarbodiimide (DCC) and 50 mg of 4-(dimethylamino)pyridine (DMAP) were added. The reaction mixture was stirred for 24 hours at room temperature. Then 50 ml of anhydrous hexane were added. The formed solid residue was separated by filtration under vacuum and washed with n-hexane (70 ml). The filtrate was concentrated under reduced pressure until obtaining an amorphous yellow solid, subsequently purified by flash chromatography (ligroin/ethyl acetate 9/1 v/v), yielding 14 g of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[CH:17][C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=1.C(=O)(O)[O-].[K+].O>Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[C:17]([CH:27]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[OH:28])[C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1CCCCNc1nc(=O)cc[nH]1
Reactant: O=Cc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: COc1cccnc1CCCCNc1nc(=O)c(C(O)c2ccncc2)c[nH]1

Procedure:
2-[[4-(3-Methoxy-2-pyridyl)butyl]amino]-4-(1H)-pyrimidinone (0.14 g) and pyridine-4-aldehyde (0.06 g) were refluxed in concentrated hydrochloric acid (1 ml) for 5 hours. The solution was cooled and neutralised by the addition of potassium bicarbonate. Water (2 ml) was added, the aqueous layer was then decanted from the red coloured oil which was washed with more water. The oil was subjected to chromatography on silica gel using gradient elution (100% chloroform→2% Methanol in chloroform). The fractions containing the desired product were collected, combined and evaporated under reduced pressure to afford the title compound as an oil; δ(CDCl3) 1.67 (4H, m), 2.80 (2H, t), 3.36 (2H, m), 3.80 (3H, s), 5.72 (1H, s), 7.07 (2H, d), 7.35 (2H, d), 7.49 (1H, s), 7.87 (1H, t), 8.43 (2H, m) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>COCCOC.CCCCCC.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:21][C:22]1[N:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2cccc(Cl)n2)OC1(C)C
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
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: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C)c3cc(-c4cccc(Cl)n4)cnc32)cc1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
To a stirred solution of 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (139 mg, 0.418 mmol) in 1,2-dimethoxyethane (10 mL) was added 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (99) (100 mg, 0.418 mmol) and Cs2CO3 (32 mg, 0.104 mmol). The resulting reaction mixture was degassed, purged with N2 for 15 min, Pd(PPh3)4 (19 mg, 0.0167 mmol) was added and the mixture purged again under nitrogen for another 15 min. The reaction mass was heated at 100° C. in a sealed tube for 12 h. After completion of the reaction the reaction mass was partitioned between ethyl acetate and water and the organic layer was separated and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and the solvent completely distilled off to get the crude product. The crude material was passed through 100-200 mesh silica gel eluting the pure compound at 50% ethyl acetate in hexane to yield off white colored solid compound 5-(6-chloropyridin-2-yl)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine 100 (60 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:31])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][CH:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:24])=[O:31]
Reactant: CC(Nc1ncnc2ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc12)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1ncnc2ccc(NC(=O)CCN)cc12)c1ccccc1
Yield: 46.7 %

Procedure:
250 mg of 2-[4-(1-phenyl-ethylamino)-quinazolin-6-ylcarbamoyl]-ethyl-carbamic acid t-butylester dissolved in 5 ml of methylene chloride was reacted with 5 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 50 ml of saturated aqueous sodium bicarbonate solution for 30 mins, filtered under a reduced pressure, and dried to obtain the title compound (90 mg, 52%).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:6]([N:13]1[CH2:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)[O:16][CH2:2][C:3]1=[O:4])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC(CNCc1ccccc1)c1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1COC(c2ccc(Br)cc2)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
After addition of chloroacetyl chloride (8.49 g, 75.2 mmol) in toluene (30 ml) to a ice-cooled solution of 2-benzylamino-1-(4-bromo-phenyl)-ethanol (intermediate 31, 21.85 g, 71.4 mmol) in toluene (300 ml), a solution of triethylamine (10.25 g, 101 mmol) in toluene (20 ml) was added to the mixture and stirred for one hour. Sodium methoxide (28% solution in methanol, 45.73 g, 237 mmol) in methanol (30 ml) was then added to the solution and stirred for 2 hours. Reaction was quenched by adding dilute hydrochloric acid to adjust the pH around 7.0, and partitioned between water and ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine and dried over sodium sulfate. Solvents were removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/1) to afford 4-benzyl-6-(4-bromo-phenyl)-morpholin-3-one (intermediate 32, 21.26 g, 86%) as a colorless oil.