Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.Cl.[NH2:22][CH2:23][C:24]([O:26]CC)=O>>[CH2:13]([CH:23]1[N:22]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]2[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]=2[NH:1][C:24]1=[O:26])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)CN
Reactant: CCOc1cc(N)c(C(=O)c2ccccc2)cc1OC
Agent: Cl
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2
Yield: 55 %

Procedure:
By replacing (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa) in example XXIIaa by (2-amino-4-ethoxy-5-methoxyphenyl)(phenyl)methanone (XXIak), and ethyl glycinate hydrochloride by ethyl phenylalalinate hydrochloride, and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 190–193° C. 1H-NMR (DMSO, 200 MHz): d 1.33–1.39 (m, 3H, CH3), 3.36–3.64 (m, 3H, CH+CH2Bn), 3.73 (s, 3H, OCH3), 3.95–4.10 (m, 2H, CH2), 6.59 (s, 1H Ar), 6.77 (s, 1H Ar), 7.21–7.44 (m, 10H Ar), 10.36 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CC1=C(C(=O)O)Cc2ccccc21
Product: CC1=C(C(=O)Cl)Cc2ccccc21

Procedure:
1.0 g of 3-methylindene-2-carboxylic acid and 5 ml thionyl chloride were refluxed for 4 hours. Careful removal of the solvent by distillation under reduced pressure gave 3-methylindene-2-oyl chloride. The acid chloride dissolved in THF was dropped into a mixture of guanidine and sodium hydroxide at room temperature over a period of 10 min. and stirred for one hour. The reaction was terminated by work-up and the product was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:28]([CH2:31][CH2:32][CH3:33])([O-:30])=[O:29].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][O:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[O:18][C:17]=2[C:19]=1[CH:26]=[C:31]([N+:28]([O-:30])=[O:29])[CH2:32][CH3:33])([O-:25])=[O:24]
Reactant: CCC[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCC(=Cc1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2)[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of 1.0 g (2.45 mmole) of (2R)-(8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl 4-methylbenzenesulfonate in 15 mL of acetic acid was added 0.87 mL (9.8 mmole) of nitropropane and 0.38 g (4.9 mmole) of ammonium acetate and the mixture was heated at 80° C. under nitrogen for 6 hours. After the mixture cooled, the solvent was removed in vacuum and replaced with 200 mL of ethyl acetate. The solution was washed with 200 mL of water and the aqueous wash was back-extracted with an additional 200 mL of ethyl acetate. The combined organics were washed with 200 mL each of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to an oily yellow solid. Column chromatography on silica gel with 1:1 hexane/ethyl acetate as eluant gave 0.70 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.75 δ (1H); doublet 7.4 δ (2H); doublet 7.03 δ (1H); singlet 5.3 δ (1H); multiplet 4.45 δ (1H); multiplet 4.4 δ (1H); multiplet 4.21 δ (3H); singlet 2.45 δ (3H); quartet 2.4 δ (2H); triplet 1.0 δ (3H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C=O.Cl.CNC.CI.[Si](C#N)(C)(C)C.CC[CH2:26][CH2:27][N+:28](CCCC)(CCCC)CCCC.[F-]>C(O)(C)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:26][C:27]#[N:28])=[CH:2]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: c1cnc2[nH]ccc2c1
Agent: C=O
Agent: CNC
Agent: C[Si](C)(C)C#N
Solvent: CC(C)O
Solvent: CI
Product: N#CCc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 28.1 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (1.5 g, 12.7 mmol, 1.0 eq.) and paraformaldehyde (0.46 g, 15.2 mmol, 1.2 eq.) in isopropanol (20 mL) was added dimethylamine hydrochloride (1.24 g, 15.2 mmol, 1.2 eq). The mixture was stirred at reflux temperature for 20 minutes and then, quenched with ice and 5 M aqueous sodium hydroxide after cooling to room temperature. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4 and evaporated under reduced pressure. The gramine residue was taken up in a mixture of anhydrous dichloromethane (40 mL) and toluene (80 mL) and then, methyl iodide (1.26 mL, 20.3 mmol, 1.6 eq.) was added under an argon atmosphere. The mixture was stirred at room temperature for 12 hours and concentrated. To the residue taken up in anhydrous THF (120 mL) were added, under an argon atmosphere, TMSCN (2.39 mL, 19.1 mmol, 1.5 eq.) and TBAF (38.1 mL, 1M, 38.1 mmol, 3.0 eq.). The mixture was stirred at room temperature for 4 hours and then, concentrated under reduced pressure. The crude was taken up in ethyl acetate and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and then, dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 50:50) to afford 2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-acetonitrile as a white solid (0.56 g, 28%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:14])=[C:11]([O:26][CH3:27])[CH:10]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32]Cl.C(N(CC)CC)C.Cl>CN(C)C=O>[ClH:8].[ClH:28].[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:32][C:31]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:29]([Cl:28])[CH:30]=3)[CH2:20][CH2:19]2)=[O:14])=[C:11]([O:26][CH3:27])[CH:10]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(Cl)ccc1C(=O)NCCN1CCNCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(=O)NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of the product of step (a) (4.0 g), 3,4-dichlorobenzylchloride (1.9 ml) and triethylamine (9.0 ml) in N,N-dimethylformamide (20 ml) was stirred at room temperature. The solvent was removed and the residue purified by chromatography (dichloromethane:methanol, 1:0 to 4:1) to give an oil, which was treated with 1.0M ethereal hydrogen chloride to give the product as a solid (3.1 g), m.p. 240-41° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[S:4][N:3]=1.[F:16][C:17]([C:20]1[CH:25]=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])(F)[CH3:18].FC(C1C=C(O)C=CC=1CCC(OCC)=O)C>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:24]2[CH:23]=[CH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:20]([CH:17]([F:16])[CH3:18])[CH:25]=2)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: Cc1ccc(-c2snc(Cl)c2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1C(C)(F)F
Agent: CCOC(=O)CCc1ccc(O)cc1C(C)F
Product: Cc1ccc(-c2snc(Cl)c2COc2ccc(CCC(=O)O)c(C(C)F)c2)cc1

Procedure:
The two title compounds were prepared according to the procedure described in Example 127, following Steps 6-7, coupling [3-chloro-5-(4-methylphenyl)-1,2-thiazol-4-yl]methanol with a mixture of ethyl 3-[2-(1,1-difluoroethyl)-4-hydroxyphenyl]propanoate (255g) and ethyl 3-[2-(1-fluoroethyl)-4-hydroxyphenyl]propanoate (255h). Upon hydrolysis and purification, the desired products were each isolated as an off-white solid.
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[N:10]=[C:11]([C:14](=O)[CH2:15][CH2:16][CH2:17][N:18]2[C:26]([C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)=[C:25]3[C:20]([N:21]([CH3:36])[C:22](=[O:35])[N:23]([CH3:34])[C:24]3=[O:33])=[CH:19]2)[S:12][CH:13]=1>CO.O.C(Cl)(Cl)Cl>[Cl:8][C:9]1[N:10]=[C:11]([C:14]2[C:19]3[N:18]([C:26]([C:27]4[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=4)=[C:25]4[C:24](=[O:33])[N:23]([CH3:34])[C:22](=[O:35])[N:21]([CH3:36])[C:20]4=3)[CH2:17][CH2:16][CH:15]=2)[S:12][CH:13]=1
Reactant: Cn1ccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCCC(=O)c2nc(Cl)cs2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: Cn1ccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(Cl)cs2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Pyridine hydrochloride (6.02 g, 52.1 mmol) was added to a suspension of 6-(4-(4-chlorothiazol-2-yl)-4-oxobutyl)-1,3-dimethyl-5-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (2.33 g, 5.21 mmol) in methanol (82 ml) and water (8.17 ml) and the mixture stirred at room temperature for 3 days. The mixture was then diluted with chloroform (300 ml), washed with 1M HCl(aq) (3×100 ml) and saturated NaHCO3(aq) (100 ml). The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 50-80% EtOAc/hexane afforded a crude material which was triturated with methanol to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:21][N:22]=[C:23]=[O:24]>CCOCC>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([NH:20][C:23]([NH:22][CH3:21])=[O:24])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN=C=O
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Solvent: CCOCC
Product: CNC(=O)Nc1nc2nc(C)ncc2cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of 3.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-amine in 20 ml of methyl isocyanate is heated at reflux for 3 hours to obtain a yellow solution. This is stirred overnight at room temperature and diluted with 20 ml of ether. The solvent and excess isocyanate are evaporated and the solid residue of crude product is purified by recrystallization from ethyl acetate to give N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-yl]-N'-methylurea, mp 168°-171° C. (dec.).
Reaction SMILES: COP([CH2:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)(=O)OC.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][C:31]=1[CH:40]=O.[OH-].[Na+]>C1COCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:15]2[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:29])[CH:7]=[CH:40][C:31]3[CH:32]=[N:33][C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:30]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=1
Reactant: O=Cc1cnc2ccccc2n1
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)CP(=O)(OC)OC)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3cnc4ccccc4n3)n2)cc1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a solution of 6-7 (12.0 g, 28.5 mmol) and quinoxaline-2-carbaldehyde 22-1 (4.51 g, 28.5 mmol) in THF (250 mL) at 0° C. was added 4M NaOH (7.49 mL, 29.9 mmol) dropwise. After 15 minutes the ice bath was removed and the mixture stirred for an additional 10 minutes. The solution was diluted with water, extracted with ethyl acetate, and dried (Na2SO4). Following concentration, the residue was triturated with ether to give 11.4 g (88%) of 22-2 as a white solid.
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[Mg]Br.Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH3:25].P.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(COC2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2OCP(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)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[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH3:25]
Reactant: Cc1ccc2ccccc2c1[Mg]Br
Reactant: Cc1ccc2ccccc2c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2ccccc2c1-c1c(C)ccc2ccccc12
Temperature: 80 °C

Procedure:
2-Methyl-1-naphthylmagnesium bromide prepared according to Example 1 in toluene is added in the absence of air and moisture to a suspension, heated to 70° to 80° C., of 31.0 g (0.14 mol) of 1-bromo-2-methylnaphthalene, 0.0014 mol of the phosphine of the formula (I) 1,4-bis(diphenylphosphino)butane; 2,2'-bis(diphenylphosphinomethoxy)-1,1'-binaphthyl! or 0.0028 mol of the phosphine of the formula (II) (triphenylphosphine) and 0.31 g (0.0014 mol) of palladium(II) acetate in 50 ml of toluene. The mixture is then heated at 80° C. for another hour, cooled to 25° C., and 100 ml of water and 50 ml of 2N hydrochloric acid are added in succession to the reaction mixture. The phases are separated, the aqueous phase is extracted with 50 ml of toluene, and the combined organic phases are concentrated in vacuo. Distillation of the oily, brown residue in a high vacuum gives a pale yellow oil having a boiling point of 175° to 180° C./0.1 to 0.2 mbar. The yields can be found in Table 1 below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[N+:23]([O-])=O)[N:19]([CH3:26])[C:18](=[O:27])[C:17]2([CH3:29])[CH3:28])=O>[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[NH:13][C:14]2=[CH:15][C:16]3[C:17]([CH3:29])([CH3:28])[C:18](=[O:27])[N:19]([CH3:26])[C:20]=3[CH:21]=[C:22]2[N:23]=1
Reactant: CN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccc(Cl)cc3Cl)c([N+](=O)[O-])cc21
Agent: [Ni]
Product: CN1C(=O)C(C)(C)c2cc3[nH]c(CCc4ccc(Cl)cc4Cl)nc3cc21

Procedure:
2-[2-(2,4-Dichloro-phenyl)-ethyl]-5,7,7-trimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one is prepared from 3-(2,4-dichloro-phenyl)-N-(1,3,3-trimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-propionamide as described in Example 1b using Raney-nickel (71 mg) instead of Pd/C (497 mg).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1OS(C)(=O)=O.[C:15](#[N:17])C>[C-]#N.C([N+](CC)(CC)CC)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:15]#[N:17]
Reactant: CC#N
Reactant: CS(=O)(=O)OC1Cc2ccccc2C1
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: N#CC1Cc2ccccc2C1
Temperature: 55 °C
Yield: 52 %

Procedure:
A mixture of methanesulfonic acid indan-2-yl ester (18.65 g, 87.9 mmol) and tetraethylammonium cyanide (15.10 g) in acetonitrile (180 mL) was heated to 55° C. for 5 hours, cooled and concentrated. The residue was partitioned between ethyl acetate and water, and the organic phase separated. This was dried over MgSO4 and the filtered solution was concentrated and then separated by column chromatography (dichloromethane:ethyl acetate, 6:1-1:1) to give the product as a red solid (6.51 g, 52%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:2]=1.O1CCCC1.CC(C)([O-])C.[K+].Br[CH2:37][CH2:38][N:39]1[C:44](=[O:45])[C:43]2[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=2[N:41]=[N:40]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(O)(C)(C)C>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9](=[O:18])[CH:10]([CH2:37][CH2:38][N:39]2[C:44](=[O:45])[C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[N:41]=[N:40]2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:6]=1
Reactant: O=c1c2ccccc2nnn1CCBr
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)C(CCn1nnc2ccccc2c1=O)C(=O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
To a solution of the compound (300 mg) obtained from step 1 above in dry tetrahydrofuran (4 ml) and tert-butanol (4 ml) at 0° C. was added potassium tert-butoxide (104 mg) and stirred for 20 minutes. To the resulting reaction mixture was added 3-(2-bromoethyl)-1,2,3-benzotriazin-4(3H)-one (235 mg) and tetrabutylammonium iodide (349 mg) and the mixture was further stirred for 30 minutes at 0° C., followed by stirring at room temperature for 30 minutes and finally at 80° C. for about 5-6 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluant to furnish the title compound (240 mg).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].O1CCOCC1.[C:16]1([CH2:22][O:23][CH2:24][CH:25](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([CH2:22][O:23][CH2:24][CH:25]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])[CH3:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCCCCO
Reactant: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(COCc1ccccc1)OCCCCCO
Temperature: 80 °C
Reaction time: 20 h
Yield: 37.1 %

Procedure:
Into another flask, KOH (25.8 g), HO(CH2)5OH (47.9 g) and dioxane (200 ml) were charged and stirred at 90° C. until KOH was dissolved. Then, from a dropping funnel, PhCH2OCH2CH(CH3)OTs (71.2 g) and dioxane (75 ml) were added at 90° C. over a period of 20 minutes. After further stirring at 80° C. for 20 hours, water (350 ml) was added. Extraction with dichloromethane (100 ml) was carried out three times, and the extracted organic phase was washed with water (150 ml), then dried over anhydrous magnesium sulfate, filtered and further concentrated. The concentrated liquid was purified by silica gel column (eluent: hexane/ethyl acetate) to obtain PhCH2OCH2CH(CH3)O(CH2)5OH (20.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.CC(C)([O-])C.[K+].[CH3:35][C:36]1[S:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:42][CH2:41][C:39]2[N:40]=[C:36]([CH3:35])[S:37][CH:38]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCCO2
Reactant: Cc1nc(CO)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1nc(COc2nc(N)c(C#N)c(-c3ccc4c(c3)OCCO4)c2C#N)cs1

Procedure:
100 mg (0.26 mmol) of 2-amino-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile [prepared analogously to Kambe et al., Synthesis, 531-533 (1981)] are, together with 44 mg (0.39 mmol) of potassium tert-butoxide and 334 mg (2.59 mmol) of (2-methyl-1,3-thiazol-4-yl)methyl alcohol, stirred in 5 ml of 1,2-dimethoxyethane at room temperature overnight. The reaction solution is concentrated under reduced pressure and the residue is then purified by preparative HPLC on reversed-phase silica gel.
Reaction SMILES: C1(=O)N(CC#N)C(=O)C2=CC=CC=C12.CC(O)(CCCC)C.S(=O)(=O)(O)O.[CH3:28][C:29]([NH:35][C:36](=[O:49])[CH2:37][N:38]1C(=O)C2=CC=CC=C2C1=O)([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33].O.NN>C(O)(=O)C.C(O)C.C1C=CC=CC=1>[NH2:38][CH2:37][C:36]([NH:35][C:29]([CH3:28])([CH3:34])[CH2:30][CH2:31][CH2:32][CH3:33])=[O:49]
Reactant: CCCCC(C)(C)NC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CCCCC(C)(C)O
Agent: N#CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC(C)(C)NC(=O)CN

Procedure:
2-Phthalimidoacetonitrile (14.4 g.) was reacted with 2-methylhexan-2-ol (7.5 g.) in glacial acetic acid by the addition of concentrated sulphuric acid (15 ml.) according to the process described in Example 1. The resulting N-(1,1-dimethylpentyl)-2-phthalimidoacetamide was recrystallisedfrom benzene, m.p. 189°-190° C. It was then reacted with hydrazine hydrate (2.8 g.) in ethanol (100 ml.) as in Example 2 and the product purified as its hydrogen oxalate; 2-amino-N-(1,1-dimethylpentyl)acetamide hydrogen oxalate.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]2[NH:8][C:9]3[N:10]([N:11]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:19][CH:18]=4)[C:13]=3[C:14]([NH2:16])=[O:15])[C:6]=2[CH:5]=1)([O-])=O>CC(O)=O.[Zn]>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]2[NH:8][C:9]3[N:10]([N:11]=[C:12]([C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:21][CH:22]=4)[C:13]=3[C:14]([NH2:16])=[O:15])[C:6]=2[CH:5]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c1ccc([N+](=O)[O-])cc12
Agent: [Zn]
Solvent: CC(=O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c1ccc(N)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To a solution of 7-nitro-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide (9 mg, 0.022 mmol) in 3 mL of HOAc was added zinc powder (14 mg, 0.22 mmol). Then the mixture was stirred at RT for 20 min, until TLC and LCMS analysis showed that most of starting material was consumed. The reaction solid was filtered off. The filtrate was concentrated, suspended in 10 mL of EA and filtered. The filtrate was concentrated to get the product as a white solid (4 mg, 50%). 1H NMR (400 MHz, CD3OD-d4) δ 7.60 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (s, 1H), 7.08 (t, J=8.0 Hz, 1H), 7.05-6.95 (m, 4H), 6.79 (dd, J=1.6, 8.4 Hz, 1H). MS (ESI) m/e [M+1]+ 384.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([CH:11]1[NH:16][C:15](=O)[CH2:14][C:13](=[O:18])[CH2:12]1)[CH:8]([CH3:10])[CH3:9]>C1COCC1>[CH2:7]([CH:11]1[CH2:12][CH:13]([OH:18])[CH2:14][CH2:15][NH:16]1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CC1CC(=O)CC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1CC(O)CCN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred ice cooled suspension of LAH (16.1 g, 0.414 mol) in THF (100 mL), a solution of 6-isobutyl-piperidine-2,4-dione (14.0 g, 0.083 mol) in THF (100 mL) was added dropwise under N2. The reaction mixture was warmed to room temperature and stirred under N2 for 48 h. The reaction mixture was cooled to 0° C. and quenched with water (16.1 mL), 1 N NaOH (16.1 mL) and water (16.1 mL). The reaction mixture was filtered and the solid was washed with hot THF (100 mL). The filtrate was concentrated to yield 2-isobutyl-piperidin-4-ol as a solid (9 g, crude).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:16]([CH2:17][C:5]2=1)[CH2:15][CH2:14][CH2:13]3.ClC1C=CC2NC3CCN4C(C=3C=2C=1)CCC4.Br[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.C(N(CC)CC)C>CCO.CCOC(C)=O>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]3[CH2:17][N:16]4[CH:12]([CH2:11][C:6]2=3)[CH2:13][CH2:14][CH2:15]4)=[CH:39][CH:40]=1
Reactant: Clc1ccc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: Fc1ccc(CCBr)cc1
Agent: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN2CCCC2C3)cc1

Procedure:
A mixture of 7-chloro-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole and 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (non-separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and 1-(2-bromoethyl)-4-fluorobenzene (577 mg, 2.84 mmol, 1.4 equiv) were heated to 95° C. with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6 mL of EtOH for 18 h. The mixture was brought to RT followed by dilution with EtOAc (40 mL), washed with water (2×10 mL), then with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over 230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%). The product was further purified by reverse phase HPLC.