Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[CH:26]=[O:27])[C:17]#[N:18].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C@:36]([OH:51])([C@H:43]([S:45][CH:46]([CH2:49]O)[CH2:47][OH:48])[CH3:44])[CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1>ClCCl>[C:17]([C:16]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[C@H:26]2[O:48][CH2:47][C@H:46]([S:45][C@H:43]([CH3:44])[C@:36]([C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])([OH:51])[CH2:37][N:38]3[CH:42]=[N:41][CH:40]=[N:39]3)[CH2:49][O:27]2)=[C:14]([F:13])[CH:15]=1)#[N:18]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
791 mg (4.16 mmol) of p-toluenesulfonic acid monohydrate were added to a solution of 760 mg (3.77 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]-benzonitrile [obtained as described in Example 1(ii) above] and 1.36 g (3.77 mmol) of (2R,3 R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2 -hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350] in 13 ml of dichloromethane. The resulting mixture was concentrated using a rotary evaporator. 13 ml of dichloromethane and 13 g of 4A molecular sieves were added to the resulting residue and the mixture was then stirred at ambient temperature overnight. At the end of this time, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The molecular sieves were removed by filtration and the filtrate was partitioned between ethyl acetate and water. The organic layer was dried and concentrated under reduced pressure. The resulting oil residue was purified by chromatography on a silica gel (20 a) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to afford 1.42 g (yield 69%) of the title compound as an amorphous solid. The spectral data were identical to those of the title compound of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1>C(O)(=O)C.[Pt]=O>[NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[NH:3]1
Reactant: Nc1cccc(Cc2ccccc2)n1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: N=C1CCCC(CC2CCCCC2)N1

Procedure:
The 2-amino-6-benzylpyridine product of Example 298 A was reduced in acetic acid under hydrogen atmosphere utilizing platinum oxide catalyst to afford 2-imino-6-cyclohexylmethylpiperidine as an oil. The oil was dissolved in 1N HCl and lyophilized to give a white solid. The solid was recrystallized from EtOAc to give the title product as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[CH:5]=[N:6][C:7]=1[Cl:8].Cl.CCOCC.C(Cl)(=O)C(Cl)=O.Cl.[NH:25]1[CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[N:25]1([C:9]([C:4]2[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[O:11])[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
5,6-Dichloropyridine-3-carboxylic acid (CAS no. 41667-95-2) (32 g, 0.17 mol) was suspended in DCM (500 mL) and 1M HCl in ether (0.17 L, 0.17 mol) added. Oxalyl chloride (17 mL, 0.20 mol) and then DMF (2 drops) were added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene and re-dissolved into DCM (250 mL). Azetidine hydrochloride (17.5 g, 0.18 mol) was added, followed by triethylamine (51 mL, 0.37 mol) and the reaction stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure then water (500 mL) and ethyl acetate (500 mL) were added. The organic layer was separated and the aqueous phase was re-extracted with ethyl acetate (5×150 mL). The combined organics were washed with citric acid (250 mL), saturated sodium bicarbonate solution (250 mL), brine (250 mL), dried (MgSO4), filtered and evaporated under reduced pressure to give a solid which was recrystallised in ethyl acetate and dried under reduced pressure to give the product (18.2 g, 47%). 1H NMR δ (400 MHz, CDCl3) 2.34 (quintet, 2H), 4.20 (s, 2H), 4.27 (s, 2H), 8.02 (d, 1H), 8.44 (d, 1H); m/z 231 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH2:16](O)[CH3:17]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(O)nc1
Reaction time: 6.5 h
Yield: 89 %

Procedure:
To a solution of 6-hydroxynicotinic acid (5.0 g, 35.9 mmol) in ethanol (180 mL), sulfuric acid (1.0 mL) was added. The resultant mixture was stirred at 60° C. for 20 minutes, then added with surfuric acid (33.0 mL), and stirred for 6.5 hours while heated to reflux. The reaction solution was then added with a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions and ethanol was concentrated in vacuo. After extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Ethyl 6-hydroxynicotinate (5.33 g, yield 89%) was obtained as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:13][Br:14])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(Cl)nc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)cc(Cl)nc1CBr

Procedure:
To a solution of 710 mg, (3.6 mmol) 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester in CCl4 (16 ml) were added 688 mg (3.90 mmol) N-bromosuccinimide, 59 mg (0.36 mmol) AIBN and 210 μl (3.72 mmol) acetic acid. The reaction mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. The mixture was then filtered through celite, washed with CCl4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue a mixture of 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester, 4-(bromomethyl)-6-chloro-2-methyl-pyridine-3-carboxylic acid methylester and 2-(bromomethyl)-6-chloro-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This mixture was dissolved in dioxane (10 ml) and added at 0° C. to a solution prepared by dissolving 594 mg (25.8 mmol) sodium in MeOH (11 ml) at 0° C. This reaction mixture was stirred at RT for 3 h. Then the reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue again a mixture of 6-chloro-4-(methoxymethyl)-2-methyl-pyridine-3-carboxylic acid methylester and 6-chloro-2-(methoxymethyl)-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This material was dissolved in NMP (7.8 ml) and 860 μl (9.85 mmol) morpholine and 1.36 g (9.85 mmol) K2CO3 were added followed by heating at 100° C. for 5 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 90 mg (0.32 mmol, 9%) 2-(methoxymethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].[H-].[Na+].[CH2:11]=[CH:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C:6](=[O:7])[NH:5][N:4]([CH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]1=[O:8]
Reactant: Cn1c(=O)[nH][nH]c1=O
Reactant: C=CC(=O)CCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(=O)CCn1[nH]c(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 54.3 %

Procedure:
To a solution of 4-methyl-1,2,4-triazolidine-3,5-dione (5.75 g, 0.05 mol) in dry dimethylformamide (40 ml) stirred at 75° under a nitrogen atmosphere was added portionwise sodium hydride (1.575 g, 0.055 mol, as an 80% dispersion in mineral oil) and the resultant solution stirred at 75° for 0.5 hr. To this solution was added oct-1-en-3-one (6.57 g, 0.055 mol) dropwise in dimethylformamide (20 ml) and the solution heated with stirring for 48 hr at 75°. The reaction mixture was then cooled, taken up in ethyl acetate (100 ml) and poured into ice-cold 5N aqueous hydrochloric acid (200 ml). The aqueous layer was separated and extracted with ethyl acetate (4×100 ml). The combined extracts were washed with 5N aqueous hydrochloric acid, water and then brine, then dried (Na2SO4), filtered and the solvent removed by evaporation in vacuo, to leave a gum (6.55 g). This was chromatographed on silica gel (Merck, Kieselgel 60) with a packing ratio of 1:20 with chloroform as eluant, to afford the triazolidine-3,5-dione (4.61 g) as a gum, which later solidified. (In subsequent preparations the crude material from the reaction mixture could be triturated with hexane to induced crystallisation), m.p. 76°-8°.
Reaction SMILES: O=C1C2N=CN=CC=2C=C2OCNC12.[OH:15][C:16]1[C:17]([N+:28]([O-])=O)=[CH:18][C:19]([N+:25]([O-])=O)=[C:20]([CH:24]=1)[C:21]([NH2:23])=[O:22]>[Pd]>[NH2:25][C:19]1[CH:18]=[C:17]([NH2:28])[C:16]([OH:15])=[CH:24][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)c1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C1c2ncncc2C=C2OCNC12
Product: NC(=O)c1cc(O)c(N)cc1N

Procedure:
Scheme 2 can be illustrated with reference to the preparation of 4-oxo-3H-oxazolo[5,4-g]quinazoline. In this process, 5-hydroxy-2,4-dinitrobenzamide (compound of formula VIII in which Y1 is amino, Y2 is O, Y4 is hydroxy and Y5 is nitro) is hydrogenated over 5% palladium over carbon at about 60 psi for about 3 hours to give 2,4-diamino-5-hydroxybenzamide. To this product is added formic acid and the mixture is heated to reflux for about 48 hours to provide 4-oxo-3H-oxazolo[5,4-g]quinazoline. In this process, steps 1 and 2 of Scheme 2 are performed as a single step.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:27]=[C:26]([O:28]C)[CH:25]=[CH:24][C:12]=3[C:13]=2[C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:12]=3[C:13]=2[C:14](=[O:23])[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 10 °C
Reaction time: 24 h

Procedure:
A mixture of 53 g. of the product of Example 9 in dry chloroform was prepared. The mixture was cooled to 10° C., and 75 g. of boron tribromide were added. The mixture was stirred for 24 hours at room temperature. The mixture then was poured into water, the chloroform layer was separated, and the aqueous layer was extracted with additional chloroform which was added to the separated chloroform layer. The resulting chloroform mixture then was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in benzene, the benzene solution was filtered, concentrated to dryness, and the residue was chromatographed on silica using 10 percent ether in benzene as eluant. Those fractions containing material having the same Rf value were combined and rechromatographed on alumina using ether as solvent followed by a mixture of 10 percent methanol in ether. The title compound (5.8 g.) was obtained, melting point 138°-140° C.
Reaction SMILES: [OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17](=[CH:18][C:19](=[O:20])[CH:21]=[CH:22]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:3])[CH3:4]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 149.5 %

Procedure:
25-Hydroxycholesterol (I) (10.0 gm, 0.0248 mol) was dissolved in 290 ml of dry dioxane. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (18.62 gm, 0.082 mol) was added and the reaction was refluxed 14 hours. The reaction mixture was allowed to cool and then filtered. The filtrate was concentrated, in vacuo, to give 14.7 gm red-brown solid. This solid was taken up in 40 ml ethyl acetate and chromatographed on 250 gm neutral alumina, eluting with ethyl acetate. Product-containing fractions were combined, concentrated and recrystallized from 50 ml ethyl acetate giving 5.80 g of the title compound (58%): m.p. 179.5°-181.5° C.; nmr (CDCl3): δ0.76 (s,3H,C19CH3), 1.20 (s,9H,C18 +C26 +C27CH3 's), 2.04 (s,1H,OH), 6.10 (m,4H,C2 +C4 +C6 +C7H's), 7.10 (d,J=12 Hz, 1H,C1H); UV (ethanol) λmax 225, 257, 299 nm.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:8]=1[CH:9]=[N:10][OH:11])[CH:5]=[CH2:6].C([O-])(=O)C.[Na+]>C(Cl)Cl>[Cl:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:7]2[C:8]=1[C:9]1=[N:10][O:11][CH2:6][CH:5]1[CH2:4]2
Reactant: C=CCc1cccc(Cl)c1C=NO
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Clc1cccc2c1C1=NOCC1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At room temperature, 37.0 ml of a sodium hypochlorite solution (12.5% of active chlorine) were added dropwise to a solution of 8.4 g (42.9 mmol) of 2-allyl-6-chlorobenzaldehyde oxime in 100 ml of methylene chloride, and a spatula tip of sodium acetate was added. The mixture was stirred at room temperature for 2 hours, the organic phase was separated off, the aqueous phase was extracted with methylene chloride and the combined organic phases were washed with saturated ammonium chloride solution. The organic phase was dried and the solvent was removed. This gave 7.0 g (94%) of 8-chloro-3a,4-dihydro-3H-indeno-[1,2-c]isoxazole in the form of a viscous oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC>[C:17]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)c1cccc(-c2ccccc2)n1
Yield: 2.5 %

Procedure:
Preparation H9, Step 1: 6-Bromopicolinic acid (1.0 g) was dissolved in 1,2-dimethoxyethane (15 mL) prior to the addition of palladium tetrakistriphenylphoshine (572 mg), 2M Na2CO3 (5 mL), and phenyl boronic acid (905 mg). The resulting solution was heated at reflux for 48 h. After cooling, 1N HCL was added to adjust the pH<4. A white precipitate was formed and was removed by filtration. A small portion of the filtrate was purified by reverse phase HPLC (gradient elution, water/acetonitrile/TFA) to afford 6-phenylpicolinic acid (25 mg). MS found: (M+H)+=200.1.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13]C.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[OH:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a solution of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (2.0 g, 10.15 mmol) in anhydrous CH2Cl2 (10 mL) was added boron tribromide (4 mL) at 0° C. Reaction was warmed to room temperature and stirred for 2 hour under N2. Followed a standard aqueous/EtOAc workup. The residue was purified by silica gel column chromatography (1.2 mg, yield: 64.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)O)ncn2-c2cccc(Cl)c2C1=O

Procedure:
A mixture of 37.3 g (116.6 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 5.276 g (131.9 mmol) of sodium hydroxide, 150 ml of ethanol and 100 ml of water is heated to boiling under reflux for 15 minutes. The mixture is then neutralized by the addition of 132 ml of 1N hydrochloric acid, the ethanol is distilled off in vacuo and the residue is diluted with 100 ml of water. The mixture is cooled to about 0°, the product is filtered off under suction, rinsed with water and dried at 80° in a high vacuum. There is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 283°-284°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH:18]=O)[N:5]([CH:16]=O)[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.C([O-])(=O)C.[NH4+:25].C(O)(=O)C>O>[CH3:1][O:2][C:3]([C:4]1[N:5]([CH:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH2:7]2)[CH:16]=[N:25][CH:18]=1)=[O:20]
Reactant: [NH4+]
Reactant: COC(=O)C(C=O)N(C=O)C1CCCc2ccccc21
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cncn1C1CCCc2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 16.5 g of N,α-bis-formyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl) glycine methyl ester, 65.0 g of ammonium acetate and 100 ml of acetic acid are refluxed for 8 hours. Then additional 50 g ammonium acetate are added and the refluxing is continued for further 4 hours. The solution is diluted with 300 ml of water and extracted twice, with 100 ml of toluene each time. The organic phases are combined, concentrated and separated at silica gel by chromatography. Concentration of the eluate yields 1-(1,2,3,4-tetrahydronaphthalen-1-yl) -5-imidazolecarboxylic acid methyl ester, having a melting point of 63° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C=O)C>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2oc2c(Cl)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3ccccc3oc2c1Cl
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 1.2 g of 4-chloro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g of potassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF was stirred at 60°-70° C. for 3 hours. After cooling the mixture, water was added and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.1 g of ethyl 4-chloro-9-oxo-9H-xanthene-3-yloxyacetate. m.p. 183°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CBr)c(C(F)(F)F)c1
Yield: 98.1 %

Procedure:
4-methyl-3-(trifluoromethyl)benzonitrile (10 g, 54 mmol) was dissolved in 200 mL of carbon tetrachloride and treated with N-bromosuccinimide (10.5 g, 59 mmol) and benzoyl peroxide (1.3 g, 0.54 mmol). The reaction mixture was heated to reflux temperature and stirred for one week. Then, 80 mL of water was added and the layers were separated. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with water (2×50 mL), dried over magnesium sulfate, and concentrated to provide 4-(bromomethyl)-3-(trifluoromethyl)benzonitrile (14 g, 53 mmol) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH2:19])=O)=[CH:10][CH:9]=1.O.[OH-].[Na+]>C(OCC)C.C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:19])=[CH:12][CH:13]=1
Reactant: NC(=O)CCCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NCCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
(Ali, F. E.; Dandridge, P. A.; Gleason, J. G.; Krell, R. D.; Kruse, C. H.; Lavanchy, P. G; Snader, K. M. J. Med Chem., 1982, 25, 947). To a stirred suspension of lithium aluminum hydride (2.40 g, 63.2 mmol) in 65 mL diethyl ether was added slowly a solution of (3.12 g 15.8 mmol) of 36a in 28 mL THF, and stirred at rt for 1 h. To the reaction mixture was slowly added 4 mL water, 4 mL 5 N NaOH(aq), and 12 mL water. The organics were removed from the emulsion which was dissolved in water and extracted with ether. The organic portions were dried over Na2SO4(s), and condensed to give 37a (2.76 g, 95%) as an oil. UV λmax 224 (7600, 95% ETHANOL). 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 2H), 7.10 (d, J=8 Hz, 2H), 2.74 (t, J=7 Hz, 2H), 2.60 (t, J=8 Hz, 2H), 2.25 (s, 2H), 1.64 (m, 2H), 1.49 (m, 2H). 13C NMR (CDCl3) δ 141.2, 131.8, 130.1, 128.8, 42.3, 35.4, 33.6, 29.0; IR (liq.) 3365 (b), 3296 (b), 3026, 2933 (s), 2858 (s), 2170 (w), 1996 (w), 1576, 1492 (s), 1460, 1093 (s), 1016 (s), 831, 821, 804, cm−1; HRMS (FAB) calcd for C10H14ClN+H1 184.0893, found 184.0879.
Reaction SMILES: [Cu:1](Cl)Cl.[NH2:4][NH:5][C:6]([NH:8][NH2:9])=[O:7].[H-].[K+]>O1CCCC1>[NH2:4][NH:5][C:6]([NH:8][NH2:9])=[O:7].[NH2:4][NH:5][C:6]([NH:8][NH2:9])=[O:7].[Cu+2:1]
Reactant: Cl[Cu]Cl
Agent: NNC(=O)NN
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: [Cu+2]

Procedure:
Treatment of anhydrous copper(II) chloride with two equivalents of LtBu,NMe2K, LiPr,NMe2K or LMe,NMe2K, prepared in situ from the corresponding carbohydrazide ligands and potassium hydride, in tetrahydrofuran afforded the mononuclear copper(II) bis-carbohydrazide complexes Cu(LtBu,NMe2)2 (32, 75%), Cu(LiPr,NMe2)2 (33, 51%), and Cu(LMe,NMe2)2 (34, 23%), respectively, as maroon crystals (eq 9). Compound 32 was isolated in high yield from sublimation at 70° C./0.05 Torr, whereas sublimation yields for 33 (75° C./0.05 Torr) and 34 (80° C./0.05 Torr) were substantially lower. Similar treatment of cobalt(II) chloride with LtBu,NMe2K afforded Co(LtBu,NMe2)2 (35, 57%) as red crystals upon sublimation at 75° C./0.05 (eq 9). Treatment of the mono acetonitrile adduct of nickel(II) chloride with two equivalents of LtBu,NMe2K or LiPr,NMe2K afforded the mononuclear bis-carbohydrazide complexes Ni(LtBu,NMe2)2 (36, 76%) and Ni(LiPr,NMe2)2 (37, 62%), respectively, as orange color crystals upon sublimation at 70° C. and 80° C./0.05 Torr, respectively (eq 10).