Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:19]/[C:20](=[O:21])[CH3:22])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)/C=C/c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
In a 250 ml single neck flask was charged 14 g (99.6 mmoles, 1.0 eq) of p-chlorobenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 15.5 g of (E)-4-(4-chlorophenyl)-3-buten-2-one as a faintly yellow oil in 86.2% yield.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].C([O-])(=O)C.[NH4+].Cl>C(O)C.O>[C:2]1([C:1]([CH2:9][C:10]#[N:11])=[C:13]([C:12]#[N:16])[C:14]#[N:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC#N
Reactant: N#CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#CCC(=C(C#N)C#N)c1ccccc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of 250 grams (1.722 mol, 1 eq) of benzoylacetonitrile, 284 grams (270 mL, 4.306 mol, 2.5 eq) of malononitrile and 138 grams (1.784 mol, 1.04 eq) of ammonium acetate in 2500 mL of ethanol was heated to reflux for 1.5 hours and then cooled to room temperature. To this mixture was added 190 mL of 12M hydrochloric acid dropwise with cooling (ice/water bath). The mixture was placed in a separate flask and a solid formed. To this mixture was added 3300 mL of water with stirring. The solid was collected and washed with 2 liters of water and stirred with 1200 mL of ethanol to give 203.3 grams (61% yield) of product.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:23][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Yield: 79.3 %

Procedure:
4-(Phenylmethoxy)benzoic acid. In a modification of the literature method [E. L. Elied, R. P. Anderson, Reactions of esters with targeting amines. I. Benzyl esters from methyl esters and benzyldimethylamine, J. Am. Chem. Soc., 1952, 74, 547-549] a mixture of 4-hydroxybenzoic acid (27.6 g, 200 mmol), chloromethylbenzene (57.0 g, 450 mmol), potassium carbonate (50 g) and sodium iodide (25 g) was boiled under reflux in acetonitrile (500 mL) for 16 h. The suspension was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was recrystallised from ethanol to give phenylmethyl 4-(phenylmethoxy)benzoate (48.8 g, 76%). Phenylmethyl 4-(phenylmethoxy)benzoate (48.8 g, 150 mmol) was boiled under reflux with aqueous sodium hydroxide (2M; 250 mL) and ethanol (250 mL) for 4 h. The ethanol was evaporated under reduced pressure. Water (1000 mL) was added. The white solid was collected by filtration, warmed to 65° C. with aqueous sulphuric acid (2M; 300 mL) for 1 h and extracted with warm ethyl acetate. The ethyl acetate solution was dried with anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give 4-(phenylmethoxy)benzoic acid (27.15 g, 80%). The filtrate was washed twice with diethyl ether, acidified by addition of sulphuric acid (2M) and extracted with diethyl ether. Evaporation of the diethyl ether gave a further portion of 4-(phenylmethoxy)benzoic acid (6.0 g, 18%). The total yield was 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](F)[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Fc1cccc(F)n1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(F)n1

Procedure:
The title compound, MS: m/e=312.0, 314.0 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2,6-difluoro-pyridine.
Reaction SMILES: Cl.NO.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][N:19]3[CH:25]=2)=[CH:12][CH:11]=1)=[O:9]>C(O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:25]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([C:8]4[O:9][N:5]=[CH:6][CH:7]=4)=[CH:11][CH:12]=3)[N:17]=2)[CH:20]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Ic1ccc2nc(-c3ccc(-c4ccno4)cc3)cn2c1
Yield: 24.9 %

Procedure:
Hydroxylamine hydrochloride (53 mg) was added to a solution (5 mL) of (E)-3-(dimethylamino)-1-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-2-propen-1-one (104 mg) in ethanol, followed by refluxing for 2 hours. The solvent was evaporated, and the residue was purified through silica gel chromatography (dichloromethane:methanol=97:3), to thereby yield the title compound (24 mg).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(=O)(O)[O-].[Na+].[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>COCCOC>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:24]2[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: NC(=O)Nc1sc(Br)cc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)Nc1sc(-c2ccc(C=O)cc2)cc1C(N)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
2-[(Aminocarbonyl)amino]-5-bromothiophene-3-carboxamide (11.75 g) was stirred in DME (500 ml) and saturated aqueous sodium bicarbonate solution (100 ml), and 4-formylphenyl boronic acid (10 g) was added. The flask was flushed with argon and tetrakis-(triphenylphosphine)palladium(0) (5.1 g) was then added. The reaction was stirred at 90° C. for 2 h, then cooled and evaporated under reduced pressure. The residue was treated with DCM (200 ml) and 2N sodium hydroxide solution (100 ml), and stirred for 20 min. The resulting solid was then isolated by filtration and purified by trituration with ethanol (100 ml), giving the product as a pale green solid (5.75 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.C(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:19][CH:20]=2)[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2[C@H](Oc2ccc(N)cc2)C[C@@H]1C
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc(NS(C)(=O)=O)cc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[Step 3] (2S,4R)-1-acetyl-4-(4-aminophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 2 mL of dichloromethane, and 28.4 μL of pyridine and 19.1 μL of methanesulfonyl chloride were added to the solution at 0° C. The mixture was stirred for 2 hours at 0° C. After completion of the reaction, the reaction mixture was diluted with chloroform, and then was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated brine. Subsequently, the resultant was dehydrated over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (hexane:acetone=2:1), and then was recrystallized from chloroform-hexane. Thus, 28.2 mg (32.0%, cis-form only) of the title compound was obtained as a pale peach-colored amorphous compound.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:46][C:47]1[C:55]2[C:50](=[CH:51][C:52]([F:56])=[CH:53][CH:54]=2)[N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:48]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[F:56][C:52]1[CH:51]=[C:50]2[C:55]([C:47]([CH2:46][CH:3]3[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:11])[C:7]4[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=4[N:5]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:4]3=[O:34])=[N:48][N:49]2[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[CH:54][CH:53]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 427 mg of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of dry DMF at 0° C. is added 2.2 mL of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture is stirred for 30 min at 0° C. and a solution of 329 mg of 3-Bromomethyl-6-fluoro-1-tert-butoxycarbonyl indazole in 2 mL of dry DMF is added dropwise. The reaction mixture is stirred overnight at RT, poured into water and the product extracted with ethyl acetate (2×15 mL). The solvent is removed in vacuo and the residue is purified by silica gel flash column chromatography (MeOH 1%:CHCl3 99%) to afford 410 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ7.85-6.91 (m, 17H), 5.01 (m, 1H,J=6.8), 4.22 (m, 3H), 3.81 (dd, 1H, J=16.5, 8.9), 3.51 (dd, 1H, J=16.5, 4.7), 1.68 (s, 9H), 1.07 (d, 6H, J=6.8).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7]>O.CC(C)=O>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6](=[O:7])[CH:8]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: O
Solvent: CC(C)=O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A suspension of 25.6 g of ferric chloride in 50 ml of water was added at room temperature to a solution of 20 g of trimethylhydroquinone in 150 ml of acetone, and the resulting mixture was stirred for 1 hour, after which it was allowed to stand for 2 days. At the end of this time, it was concentrated to about one half of its original volume, and the concentrate was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 16.9 g of the title compound having an Rf value=0.48 (on thin layer chromatography on silica gel; developing solvent: a 1:6 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C:18]([NH:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(OCC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.1 %

Procedure:
A mixture of methyl [4-({[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}amino)phenoxy]acetate (Example 200, 0.29 g, 0.64 mmol) and 1 M LiOH solution (5 mL, 5.0 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 3 h. The reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (0.29 g, quant.) as a white solid.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:2]([C:1]([NH:19][S:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:18])=[O:17])=[O:6])([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.9 %

Procedure:
To a mixture of isobutyric acid (4.6 ml, 0.05 mol), 3-nitrophenyl sulphonamide (10.1 g, 0.05 mol) and 4-dimethylaminopyridine (6.1 g, 0.05 mol) in anhydrous dichloromethane (400 ml) under an atmosphere of nitrogen was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (9.6 g 0.05 mol). The mixture was stirred at ambient temperature for 20 h. The mixture was extracted with 1M NaOH and tile separated aqueous phase was acidified using 5M HCl. The solid which precipitated was collected by filtration, washed with water and dried under vacuum to afford the title compound (8.16 g, 60%) as a colourless powder. mp 136°-138° C. 1H NMR (360 MHz, D6 -DMSO) δ 0.95 (6H, d, J=6.8 Hz), 2.48 (1H, septet, J=6.8 Hz), 7.95 (1H, dd, J=8.1 and 8.1 Hz), 8.33 (1H, dd, J=8.0 and 1.4 Hz), 8.54 (1H, dd, J=8.0, 1.4 Hz), 8.60 (1H, dd, J=1.4 and 1.4 Hz), 12.38 (1H, brs).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)C1C=CC=CC=1.[CH2:16](O)[CH3:17]>[Pd]>[CH3:10][N:11]1[CH:16]([CH3:17])[CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12]1
Reactant: CCO
Reactant: c1ccc(CN2CCC3CNCC32)cc1
Agent: [Pd]
Product: CC1C2NCCC2CN1C

Procedure:
10.8 g (46.9 mmol) of 2-benzyl-2,7-diazabicyclo[3.3.0]octane in 200 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2.5 g of palladium-active carbon. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[Cl-].[NH4+]>CO.O.[Fe]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)c(Br)c1Nc1ccccn1
Yield: 75.1 %

Procedure:
(2-Bromo-3-fluoro-6-nitro-phenyl)-pyridin-2-yl-amine (3.68 g, 11.8 mmol), iron powder (2.63 g, 47.2 mmol), and ammonium chloride (3.63 g, 70.7 mmol) in methanol (40 mL) and water (15 mL) were heated at 90° C. for 1.5 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to yield the title compound as a white solid (2.5 g, 75%). 1H NMR 400 MHz δ (CDCl3): 8.23-8.17 (1H, m), 7.48 (1H, ddd, J=8.4, 7.3, 1.9 Hz), 6.94 (1H, dd, J=8.8, 7.9 Hz), 6.77 (1H, ddd, J=7.2, 5.0, 1.0 Hz), 6.73 (1H, dd, J=8.8, 5.0 Hz), 6.31 (1H, dt, J=8.3, 1.0 Hz), 6.10 (1H, br s), 3.94 (2H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[C:14]([C:15]([O:17]C)=O)=[CH:13][CH:12]=[CH:11][N:10]=1)=O)([O-:3])=[O:2].[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[C:22]1([N:28]2[C:15](=[O:17])[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[C:7]([C:6]3[CH:19]=[CH:20][CH:21]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1cccnc1C(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: O=c1c2cccnc2c(-c2cccc([N+](=O)[O-])c2)nn1-c1ccccc1
Yield: 21 %

Procedure:
To a solution of 2-(3-nitrobenzoyl)-3-methoxycarbonylpyridine (0.26 g, 0.97 mmoles) dissolved in ethanol (50 ml), was added phenylhydrazine (0.25 ml, 2.4 mmoles). The mixture was refluxed for 168 hours. The solvent was removed and the solid was precipitated from ethanol and dried, yielding 0.07 g of 6-phenyl-8-(3-nitrophenyl) pyrido[2,3-d]pyridazin-5-one (21%), mp 167° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].Br[CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]([Cl:30])[CH:17]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:22][C:20]1[CH:21]=[C:16]([CH2:15][CH2:14][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)[CH:17]=[C:18]([Cl:30])[C:19]=1[NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CCOC(=O)CNc1c(Cl)cc(CCBr)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 58.6 %

Procedure:
To a solution of (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (495 mg) and ethyl N-[4-(2-bromoethyl)-2,6-dichloro-phenyl]aminoacetate (700 mg) in N,N-dimethylformamide (6 ml) was added N,N-diisopropylethylamine (343 μl), and the mixture was stirred for 7 hours at 70° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1) gave ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenyl]aminoacetate (510 mg).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:11])[C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)cc(C)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C#N)cc(CBr)c1Cl
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A mixture of 4-chloro-3,5-dimethyl-benzonitrile (1.011 g, 6.10 mmol), N-bromosuccinimide (1.087 g, 6.10 mmol) and benzoyl peroxide (0.074 g, 0.305 mmol) in carbon tetrachloride (30 mL) was heated to reflux for 4 hr. The reaction mixture was cooled to room temperature and filtered. The filtrate was purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexane) to give 3-bromomethyl-4-chloro-5-methyl-benzonitrile as an impure white solid (0.9938 g, 66%), which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15]O)=[NH:14])=[CH:11][N:10]=1>CN(C=O)C>[Cl:8][C:9]1[N:10]=[CH:11][C:12]([C:13]2[N:15]=[C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[O:7][N:14]=2)=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccc(Cl)nc1
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: O=C(O)CCc1nc(-c2ccc(Cl)nc2)no1
Temperature: 120 °C
Yield: 70.9 %

Procedure:
Succinic anhydride (0.39 g, 3.89 mmol) and 6-chloro-N-hydroxy-nicotinamidine (0.67 g, 3.89 mmol) were dissolved in 2 mL of DMF and heated at 120° C. for 2 h. The cooled solution was filtered and the precipitate was washed with water, and dried to give the product as 0.70 g (71%) of colorless solid which was used without further purification.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[CH:3][CH:2]=1.P(Br)(Br)[Br:16].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]=[CH:11][CH2:12][CH2:13][Br:16])=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(CCC(O)C2CC2)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: Cc1ccc(CCC=CCCBr)cc1

Procedure:
6-(p-Tolyl)-3-hexenyl bromide [V; Ar is 4-CH3C6H4, R is H] was prepared from 2-(p-tolyl)ethyl cyclopropyl carbinol (Preparation B8), phosphorus tribromide, lithium bromide and zinc bromide according to the procedure given above in Preparation C1.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[C:46](Cl)(=[O:48])[CH3:47].CO>ClCCl>[C:46]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:48])[CH3:47]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-[5-(Cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride from example D.f1 (485 mg; 1.0 mmol) and DBU (2.5 mmol) is dissolved in dry dichloromethane (5 mL). Acetyl chloride (1.1 mmol) is syringed into the reaction mixture at ice bath temperature. After addition the mixture is stirring at ambient temperature over night. Methanol (1 mL) is added and stirring is continued for two hours. The volatiles are evaporated. The residue is purified by reversed phase preparative HPLC. The collected product fraction is freeze-dried to yield the title compound as colorless solid.