Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26]1([CH:38]=[CH:37][CH:36]=[CH:35][CH2:34]1)[CH:27]=[N:28][C:29](=O)[CH2:30][CH2:31][CH3:32])C>C(Cl)(Cl)Cl>[CH3:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:29]([CH2:30][CH2:31][CH3:32])=[N:28][C:27]([C:26]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:9]1
Reactant: CCCC(=O)N=CC1(OCC)C=CC=CC1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCc1nc(-c2ccccc2)nn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Next, 8.1 g of o-tolyl hydrazine hydrochloride and 100 mL of carbon tetrachloride were put into a 500-mL three-neck flask, 7.8 g of triethylamine (Et3N) was added dropwise to this mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 11 g of N-(1-ethoxybenzylidene)butyramide obtained in Step 1 was added to the mixture, and the mixture was stirred at room temperature for 24 hours. After the stirring, the mixture was dissolved in chloroform and washed with water and saturated saline. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. This mixture was gravity-filtered, and the obtained filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography. As the developing solvent, a mixed solvent of dichloromethane and ethyl acetate in a ratio of 24:1 (v/v) was used. The obtained fraction was concentrated, so that 1-(2-methylphenyl)-3-phenyl-5-propyl-1H-1,2,4-triazole (abbreviation: HPrp3tz1-mp) was obtained (a red oily substance, 45% yield). The synthesis scheme of Step 2 is shown in (A-2) below.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)C1C=CC=CC=1.[H-].[Na+].[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>O1CCCC1>[CH:20]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:9]([OH:8])[C:10]=2[CH:11]=[CH:12]1)([CH3:22])[CH3:21]
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(O)cccc21

Procedure:
4-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour, purified by flash chromatography (98/2 ethyl acetate/hexanes), then debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:20][OH:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](OC(=O)C)(=O)[CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=3)=[C:22]([CH3:23])[O:21][N:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1F
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(-c2noc(C)c2-c2ccc(SC)cc2)cc1F
Yield: 30 %

Procedure:
3-(3-Fluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole was prepared in 30% yield from 1-(3-fluoro-4-methoxypheny]-2-[4-(methylthio)phenyl]-ethan-1-one oxime from Step 2 and acetic anhydride by the procedure described in Example 4, Step 1 and used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:12][NH:13][S:14]([OH:17])(=[O:16])=[O:15].[I:18]Cl>O.O1CCCC1.Cl>[OH:1][C:2]1[C:7]([I:18])=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:12][NH:13][S:14]([OH:17])(=[O:16])=[O:15]
Reactant: CC(C)(C)c1ccc(O)c(CNS(=O)(=O)O)c1
Reactant: ClI
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(I)c(O)c(CNS(=O)(=O)O)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-5-(1,1-dimethylethyl)phenylmethanesulfamic acid (2.6 g., 0.01 mole) in water-tetrahydrofuran (5:1; v:v; 90 ml.) is added a freshly prepared solution of iodine monochloride (1.64 g., 0.01 mole) in 3 N hydrochloric acid (12 ml.) portionwise over 5 minutes providing a dark reaction solution which is stirred at 20° C. for 2 hours and then cooled to 0°-5° C. The resulting insoluble solid is collected, washed with 12 N hydrochloric acid, dried with aspiration at 20° C. and washed with water to give crude 2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethanesulfamic acid (3.3 g., 85.9%), m.p. 172°-180° C. with dec. Recrystallization from water-ethanol (10:1; v:v) provides pure 2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethanesulfamic acid as colorless crystals, m.p. 180°-182° C. with dec.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14](=[O:18])[C:15]([OH:17])=[CH:16][C:9]=2[C:8](=[O:19])[CH:7]=1)=[O:5])C.Cl>>[O:19]=[C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:11][C:10]2[CH:12]=[CH:13][C:14](=[O:18])[C:15]([OH:17])=[CH:16][C:9]1=2
Reactant: CCOC(=O)c1cc(=O)c2cc(O)c(=O)ccc2[nH]1
Agent: Cl
Product: O=C(O)c1cc(=O)c2cc(O)c(=O)ccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-6-hydroxy-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (2.5 g, described in Example 3) and 19% hydrochloric acid (75 ml) is refluxed for 1 hour and cooled to room temperature. The crystalline precipitate is collected and washed with water, ethanol and ether to obtain the title compound, mp > 270° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11](OCC)OCC.C(O)C>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]2[O:9][CH:10]=[CH:11][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(COc1ccc(F)cc1Br)OCC
Solvent: Clc1ccccc1
Solvent: CCO
Product: Fc1cc(Br)c2occc2c1
Reaction time: 2 h
Yield: 29.6 %

Procedure:
2-Bromo-1-(2,2-diethoxy-ethoxy)-4-fluoro-benzene (60 g, 0.22 mol, Step A) was combined with Amberlyst-15 (20 g, Aldrich) in chlorobenzene (500 mL, Aldrich) and stirred with a paddle stirrer while the temperature was maintained at very gentle reflux. At the same time an azeotrope containing ethanol and chlorobenzene was removed via downward distillation. After 2 hours, more chlorobenzene was added (200 mL) and additional azeotrope was collected. The content of the flask was filtered and excess chlorobenzene was distilled (45° C., at ˜1 mm). The residue was purified by silica gel chromatography (5–10% ethyl ether/hexane) to give 7-bromo-5-fluoro-benzofuran (14 g, ˜33%) and taken to the next step. H1NMR (300 MHz, DMSOd6), ppm: 8.20 (d), 1H, 7.52 (m), 2H, 7.10 (d), 1H.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:8][C@@H:7]([CH3:18])[CH2:6][N:5]2[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[O:27])=[CH:10][CH:11]=1
Reactant: C[C@H]1CN(C(=O)c2ccccc2F)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H]1CN(C(=O)c2ccccc2F)c2cc(Br)ccc2N1
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
The crude (S)-1-(6-bromo-4-(2-fluorobenzoyl)-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone (0.686 g, 1.54 mmol) was dissolved in methanol (ca. 5-10 mL) and 10% aqueous potassium carbonate solution (23 mL, 1.7 mmol) was added. After 10 min, the reaction mixture was concentrated under reduced pressure in order to remove the methanol. The residue was then partitioned between ethyl acetate and water (ca. 5-8 mL). The organic layer was separated and washed with 5% aqueous sodium chloride solution (8 mL) and then concentrated under reduced pressure. The crude product was dissolved in toluene and concentrated. The residue was purified by column chromatography on silica gel (eluting with 4:1 hexanes-ethyl acetate followed by 2:1 hexanes-ethyl acetate) to afford (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanone (0.415 g, 77%). MS (ESI, pos. ion) m/z 349, 351 [M+1].
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[C:19]([C:13](=[CH:12][NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)C=CNc1ccccc1OC
Reactant: CCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)C(=CNc1ccccc1OC)C(=O)OCC
Temperature: -30 °C
Yield: 62.6 %

Procedure:
50% Sodium hydride (4.8 g, 0.1 mol) was washed with petroleum ether and then suspended under nitrogen in dry tetrahydrofuran (50 ml) at -30° C. Ethyl 3-(2-methoxyphenylamino)acrylate (17.4 g, 0.1 mol) in dry tetrahydrofuran (100 ml) was added dropwise to the stirred suspension keeping the temperature below -20° C. Cooling was removed and the mixture was stirred until a deep red colour was obtained. The mixture was re-cooled to -30° C. and hexanoyl chloride (13.8 ml, 0.1 mol) in dry tetrahydrofuran (50 ml) was added dropwise. Cooling was again removed and the mixture was stirred for 2 hours. The mixture was partitioned between 10% hydrochloric acid and dichloromethane then washed with water and brine, dried and evaporated to afford an oil which was chromatographed (silica gel, chloroform) to give ethyl 2-hexanoyl-3-(2-methoxyphenyl- amino)acrylate, (20 g, 62.7%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1cncc(Sc2cccc(CO)c2)c1
Product: CCCc1c(OCc2cccc(Sc3cncc(C#N)c3)c2)ccc(C(C)=O)c1O
Yield: 71.2 %

Procedure:
Using the method of Preparation 160 using 5-(3-(hydroxymethyl)phenylthio) nicotinonitrile (3.90 g, 16.1 mmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (3.13 g, 16.1 mmol) affords the title compound (4.80 g, 71%): 1H NMR (CDCl3) δ 0.92 (t, J=7.2 Hz, 3H), 1.50-1.59 (m, 2H), 2.57 (s, 3H), 2.68 (t, J=7.6 Hz, 2H), 5.18 (s, 2H), 6.43 (d, J=9.0 Hz, 1H), 7.44-7.49 (m, 3H), 7.53 (s, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.62 (dd, J=1.6, 2.3 Hz, 1H), 8.63 (dd, J=1.6, 2.3 Hz, 2H), 12.75 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C:29]1([CH3:35])[CH2:33][O:32][C:31](=[O:34])[NH:30]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[C:29]([CH3:35])([CH3:28])[CH2:33][O:32][C:31]3=[O:34])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: CC1(C)COC(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OCC4(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 14.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (785 mg) described in Preparation Example 9 and 4,4-dimethyloxazolidin-2-one (200 mg), the title compound (126 mg) was obtained.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH3:40])=[O:34])[C:15]1=[O:41].NN.O>CCO>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH3:40])=[O:34])[C:15]1=[O:41]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.155 g, 0.277 mmol) in EtOH (6.5 mL) under nitrogen was treated with hydrazine (0.218 mL, 6.92 mmol) for 7 h@50° C. The reaction was then cooled to ambient temperature and stirred overnight. After heating an additional 6.5 h@50° C. the resulting solution was poured into water (75 mL), refrigerated and the resulting suspension was filtered and washed with cold 3:1 water:EtOH. The solid was then thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (t, J=7.1 Hz, 3 H), 2.8 (t, J=7.2 Hz, 2 H), 3.5 (q, J=6.9 Hz, 2 H), 3.5 (s, 4 H), 4.2 (s, 2 H), 4.2 (t, J=7.1 Hz, 2 H), 7.1 (t, J=8.8 Hz, 2 H), 7.4 (dd, J=8.7, 5.4 Hz, 2 H), 8.1 (s, 1 H), 8.5 (s, 1 H), 10.4 (s, 1 H); ES+ MS: 429 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.Cl.[Cl:14][C:15]1[C:19]([Cl:20])=[C:18]([CH3:21])[NH:17][C:16]=1[C:22]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:23].O>CN(C=O)C>[Cl:1][C:2]1[NH:3][C:4]([N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:22]([C:16]3[NH:17][C:18]([CH3:21])=[C:19]([Cl:20])[C:15]=3[Cl:14])=[O:23])[CH2:30][CH2:29]2)([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][N:7]=1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)C=CN=C(Cl)N1

Procedure:
A solution of methyl 2,4-dichloropyrimidine-6-carboxylate (commercially available) (0.95 g, 4.6 mmol) in DMF (5 ml) was added dropwise to a solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1, 0.43 g, 4.6 mmol) and TEA (0.92 g, 9.2 mmol) in DMF (10 ml) under nitrogen. The resultant mixture was stirred for 1 h at room temperature. Water (50 ml) was added to the stirred reaction mixture and the material that precipitated was collected and washed with water/acetonitrile (1:1, 15 ml) to give 1.9 g of the title compound. An analytical sample was purified by reversed-phase HPLC (water/acetonitrile gradient, 20-95%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=1.C(OCC)(=O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[Br:10][C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[CH:18]/[CH2:19][OH:20])=[CH:15][CH:16]=1
Reactant: Clc1ccc(I)cc1
Reactant: OCC#Cc1ccc(Br)cc1
Agent: C[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC/C=C(\c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
1 M Solution of lithium aluminum hydride in tetrahydrofuran (7.9 mL, 7.9 mmol) was added to sodium methoxide (21 mg, 0.396 mmol) under nitrogen. The mixture was cooled to 0° C. and a solution of 3-(4-bromophenyl)-prop-2-yn-1-ol (1.67 g, 7.91 mmol) in dry tetrahydrofuran (12 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 3.5 h; dry ethyl acetate (2.4 mL, 15.8 mmol) was added and the whole mixture was stirred at ambient temperature for 30 min. A degassed solution of 1-chloro-4-iodobenzene (1.89 g, 7.91 mmol) in anhydrous tetrahydrofuran (12 mL), anhydrous zinc chloride (0.65 g, 4.77 mmol), tris(dibenzylidene-acetone)dipalladium chloroform complex (0.165 g, 0.16 mmol) and tri-(2-furyl)phosphine (0.184 g, 0.791 mmol) were added; the mixture was degassed and stirred at 65° C. for 22 h under atmosphere of nitrogen. The suspension was cooled down; methanol (3.5 mL) was added and the mixture was stirred for additional 1 h. The mixture was diluted with ether (40 mL) and saturated aqueous solution of ammonium chloride (2 mL), was filtered through a pad of silica gel and the pad was thoroughly washed with ether (80 mL). the filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/ethyl acetate 20:1) affording (E)-3-(4-bromophenyl)-3-(4-chlorophenyl)-prop-2-en-1-ol as yellow oil, which solidified in fridge.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2ccccc2N)cc1
Yield: 86.6 %

Procedure:
10% carbon-palladium (0.2 g) was added to an ethanol (20 ml) solution of tert-butyl[4-(2-nitrophenoxy)benzyl]carbamate (1.43 g, 4.15 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. An oil of tert-butyl[4-(2-aminophenoxy)benzyl]carbamate (1.13 g, 86.9%) was obtained.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)([O:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.8 ml of 2-p-tolylethanol are introduced into 40 ml of pyridine with ice-bath cooling, treated with 4.96 g of p-toluenesulphonyl chloride, and stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture is then slowly stirred into about 150 g of ice/water. The precipitated product is filtered off with suction, washed a number of times with water, dissolved in methylene chloride, dried over magnesium sulphate and concentrated in vacuo. 5.8 g of 2-p-tolylethyl tosylate are obtained, which is employed in the next stage without further purification.
Reaction SMILES: [C:1]([N:4]([CH2:13][C@@H:14]1[O:18][CH2:17][C@@H:16]([S:19]C(=O)C)[CH2:15]1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C[O-].[Na+].CO.Cl.C(O)(C)C>O1CCCC1>[SH:19][C@@H:16]1[CH2:17][O:18][C@@H:14]([CH2:13][N:4]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1](=[O:3])[CH3:2])[CH2:15]1
Reactant: CC(=O)S[C@@H]1CO[C@@H](CN(OCc2ccccc2)C(C)=O)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(=O)N(C[C@H]1C[C@H](S)CO1)OCc1ccccc1
Yield: 60.4 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.390 g of product from Example 72, 0.580 ml of 25% sodium methoxide/methyl alcohol, 0.850 ml of tetrahydrofuran and 1.26 ml of 2N hydrochloric acid/isopropyl alcohol to give 0.205 g of the desired product.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:5]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[NH2:1][CH:4]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N=[N+]=[N-])C2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)C2

Procedure:
1.85 g (8.97 mmol) of Lindlar catalyst (PdCaCO3) are added to a solution of 4.78 g (17.95 mmol) of tert-butyl 2-azido-7-azaspiro[3.5]nonane-7-carboxylate, obtained in step 2.1., in 70 mL of ethanol. The reaction medium is placed in a Parr flask under a hydrogen atmosphere (20 psi) at room temperature for 5 hours. The resulting mixture is filtered through Celite and the filtrate is then concentrated under reduced pressure. Water and dichloromethane are added. The aqueous phase is separated out and then extracted three times with dichloromethane, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporating off the solvent, 3.62 g of product are obtained in the form of an oil, which is used without further purification in the following step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8].[C:16]([C:18]1[S:19][C:20]([CH3:24])=[CH:21][C:22]=1[OH:23])#[N:17]>CC(C)=O>[C:16]([C:18]1[S:19][C:20]([CH3:24])=[CH:21][C:22]=1[O:23][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8])#[N:17]
Reactant: Cc1cc(O)c(C#N)s1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1cc(C)sc1C#N
Temperature: 20 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
7 g of potassium carbonate and 9.5 g of O,O-diethyl chlorothiophosphate were added to a solution of 7 g of 2-cyano-3-hydroxy-5-methyl-thiophene in 100 ml of acetone and the mixture was stirred for 15 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 11.2 g of 2-cyano-3-(diethoxythiophosphoryloxy)-5-methyl-thiophene with a refractive index of nD20 =1.534.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.Cl([O-])(=O)(=O)=O.[CH2:18]1[C:25]2[CH2:24][CH2:23][CH2:22][N+:21]=2[CH2:20][CH2:19]1.Cl>CCCCC.CCOCC.C1COCC1.CCOCC>[N:9]1[CH:8]=[C:7]([C:25]23[CH2:24][CH2:23][CH2:22][N:21]2[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Brc1cncnc1
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ncc(C23CCCN2CCC3)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17.6 %

Procedure:
A solution of 1.7M tBuLi (1.6 mL, 2.6 mmol) in pentane was added to 5-bromopyrimidine (190 mg, 1.2 mmol) in Et2O:THF (1:1, 12 mL) at -100° C. After stirring for 10 minutes, 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (500 mg, 2.4 mmol) was added to the reaction slurry, and stirring was continued for 30 minutes. The reaction mixture was then allowed to warm to 0° C. and stir for 1 hour. A solution of 2N HCl was added, and the reaction mixture was poured over Et2O and the phases separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 phases were combined, dried (MgSO4), concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (40 mg, 18%). MS (CI/NH3) m/e: 190 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.60-1.73 (m, 2H), 1.82-2.11 (m, 6H), 2.66-2.75 (m, 2H), 3.15-3.21 (m, 2H), 8.85 (s, 2H), 9.05 (s,1H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:9]([OH:16])(=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:17]([NH2:20])[CH2:18][NH2:19].[Cl-].[Zn+2:22].[Cl-]>O.[OH-].[Na+]>[Zn:22].[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:9]([OH:16])(=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:17]([NH2:20])[CH2:18][NH2:19]
Reactant: [Zn+2]
Agent: O=C(O)CCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: NCCN
Product: [Zn]

Procedure:
The zinc chelate of ethylenediamine disuccinic acid is prepared by dissolving 0.0055 moles (1.64 g) of ethylenediamine disuccinic acid in 6.0 grams of deionized water and 3.2 grams of 25 percent NaOH (sodium hydroxide). A sample, 0.005 moles (0.68 g), of zinc chloride is added with stirring. The final pH is adjusted with 25 percent aqueous NaOH solution to a pH of 7.6 and deionized water is added to obtain a final solution containing 2.8 percent chelated zinc.