Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2].B(Br)(Br)Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(OC)cc12
Agent: BrB(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(O)cc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(2-Chloro-7-methoxy-naphthalen-1-yl)-acetic acid ethyl ester (12.0 g, 43.10 mmol) and tetrabutylammonium iodide (20.7 g, 56.04 mmol) are dissolved under an atmosphere of argon in CH2Cl2 (240 ml). The reaction mixture is cooled to −78° C. and a 1 M solution of BBr3 in CH2Cl2 (108 ml, 107.77 mmol) is added during 30 minutes. After stirring at −78° C. for 15 minutes and at RT for 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NaHCO3 (8 ml) is carefully added. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 4:1 to 3:2) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, J=9.9 Hz, 3H), 4.43 (q, J=9.9 Hz, 2H), 4.48 (s, 2H), 6.28-6.36 (br, 1H), 7.29-7.32 (m, 1H), 7.48-7.49 (m, 1H), 7.58 (d, J=10 Hz, 1H), 7.89 (d, J=10 Hz, 1H), 7.96 (d, J=10 Hz, 1H). ES+-MS: 265.2, 267.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([O:13][CH3:14])[CH:7]=[CH:6]2)#[N:2].[CH2:15]([Sn:19]([N:28]=[N+:29]=[N-:30])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]3[N:28]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[N:29]=[N:30][N:2]=3)[CH:4]=2)[N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccc2cc(C#N)ccc2n1
Product: CCCC[Sn](CCCC)(CCCC)n1nnnc1-c1ccc2nc(OC)ccc2c1

Procedure:
6-Cyano-2-methoxyquinoline (0.368 g) and tri-n-butyltin azide (0.73 g) were heated together at 110° for 18 hours to afford 2-methoxy-6-(1-tributylstannyl-(1H)-tetrazol-5-yl)quinoline as a crude oil which was not purified further but was used directly in the preparation of 6-(tetrazol-5-yl)-2-(1H)-quinolone (see Example 43).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[CH2:5][O:4][N:3]=1.[NH2:13][NH2:14]>C(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][O:4][N:3]=[C:2]([NH:13][NH2:14])[C:7]=2[CH:8]=1
Reactant: ClC1=NOCc2ccc(Cl)cc21
Reactant: NN
Solvent: CCO
Product: NNC1=NOCc2ccc(Cl)cc21
Yield: 60 %

Procedure:
An amount of 3.6 g. of 4,6-dichloro-1H-2,3-benzoxazine and 1.8 ml. of anhydrous hydrazine are dissolved in 18 ml. of absolute ethanol and refluxed for 30 minutes. The mixture is allowed to cool, then is distilled in vacuo. The residue is taken up with methylene chloride and filtered from precipitated hydrazine hydrochloride. The filtered solution is distilled to dryness and the residue crystallized from ethanol. An amount of 2.10 g. of 6-chloro-4-hydrazino-1H-2,3-benzoxazine is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:17]([NH2:19])=O.C([O-])=O.[NH4+]>>[Br:16][C:14]1[CH:13]=[CH:12][C:5]2[C:6]3[C:7](=[O:8])[NH:19][CH:17]=[N:1][C:2]=3[S:3][C:4]=2[CH:15]=1
Reactant: CCOC(=O)c1c(N)sc2cc(Br)ccc12
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2sc3cc(Br)ccc3c12
Temperature: 25 °C

Procedure:
Ethyl 2-amino-6-bromo-1-benzothiophene-3-carboxylate (9.0 g, 27 mmol), formamide (85 mL) and ammonium formate (2.7 g, 43 mmol) were heated in an oil bath at 135° C. overnight. The next morning the reaction mixture was a pastel blue slurry. The reaction mixture was allowed to cool to room temperature and was then filtered. The solid was washed with water, dried by filtration, and finally dried in a vacuum oven overnight at 45° C. to yield a light blue solid (7.8 g, quantitative). 1H NMR (DMSO-d6) δ 12.9 (br, 1H), 8.37 (s, 1H), 8.35 (d, 1H), 8.31 (s, 1H), 7.69 (d, 1H); LCMS RT=3.08 min, [M+H]+=281.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([Br:18])=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=O.O.[NH2:20][NH2:21]>C(O)C>[Br:18][C:16]1[CH:15]=[N:14][C:9]2[NH:10][C:11]3[CH:12]=[N:13][C:5]([C:3]([NH:20][NH2:21])=[O:2])=[CH:6][C:7]=3[C:8]=2[CH:17]=1
Reactant: NN
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (582 mg, 1.90 mmol) and hydrazine hydrate (2.29 mL, 47.0 mmol) in ethanol (4.6 mL) was heated under reflux in an inert atmosphere. After 1 h, the reaction mixture was allowed to cool to ambient temperature. The resultant precipitate was collected by filtration, washed with ethanol, and left to air-dry to afford the title compound as a tan-yellow solid.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6](O)=[O:7].[Cl:13]C1C=C(C=CC=1O)C(O)=O>S(Cl)(Cl)=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([Cl:13])=[O:7]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(O)c(Cl)c1

Procedure:
3-Chloro-4-hydroxybenzoic acid hemihydrate (14.5 g.) was heated under reflux for 1 hour with thionyl chloride (80 ml.). The mixture was then evaporated, the residue dissolved in ether and the subsequent solution evaporated. The residue obtained (3-chloro-4-hydroxybenzoyl chloride) was dissolved in ether (80 ml.). The stirred solution was then treated dropwise with a solution of 1,2,3,6-tetrahydropyridine (16.6 g.) in ether (50 ml.) with ice-cooling. The mixture was stirred for 17 hours and evaporated. Water (150 ml.) was then added and the mixture was stirred with ether (50 ml.). The insoluble material was separated by filtration, and combined with the solid obtained by basification of the aqueous phase. The combined solids were stirred with acetone (150 ml.), separated by filtration, washed with acetone (50 ml.) and air-dried to give 1-(3-chloro-4-hydroxybenzoyl)-1,2,3,6-tetrahydropyridine (13.6 g.), m.p. 186°-189° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[S:16])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]=1[NH2:8].[CH:18](O)=O>[OH-].[Na+]>[N:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[C:7]3[N:8]=[CH:18][NH:1][C:2]=3[C:3](=[O:17])[NH:4][C:5]2=[S:16])=[CH:15][CH:14]=1
Reactant: Nc1c(N)n(Cc2ccncc2)c(=S)[nH]c1=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(=S)n(Cc2ccncc2)c2nc[nH]c12

Procedure:
The title compound was prepared in accordance with the general method described in Example 1(d), using 5,6-diamino-1-(pyridin-4-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.25 g, 1.0 mmol, obtained from Example 3(b)), with the exception that 20 minutes of reaction time in formic acid was used, followed by a reaction time of 45 minutes in sodium hydroxide (10% aq.). The title compound was obtained (0.033, 13%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:19])=O>C(OCC)(=O)C>[Cl:19][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)c2ccccc2c1CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c2ccccc2c1CC(=O)O

Procedure:
1,2-Dihydro-3-methyl-1-oxo-4-isoquinoline acetic acid (770 mg., 3.30 mmol) and phosphorous oxychloride (1.0 ml. 10.7 mmol) were refluxed in 8 ml. ethyl acetate for 16 hr then vacuum evaporated to dryness. The residue was partitioned between water and ethyl acetate. The aqueous phase was washed with ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and vacuum evaporated to yield a viscous, homogeneous oil, 1-chloro-3-methyl-4-isoquinoline acetic acid; 772 mg. (99%). This oil (623 mg., 2.65 mmol) in 6 ml. dimethylformamide was added to a solution of 3,4-dichlorobenzyl alcohol (2.75 g., 15.5 mmol) and potassium tert-butoxide (600 mg., 534 mmol) in 2 ml. dimethylformamide and the mixture was heated at 115° for 3 hr. After cooling the mixture was poured onto crushed ice and washed with 3×60 ml. ether. The basic aqueous layer was acidified to pH 3 with 1 N hydrochloric acid and extracted 3×100 ml. ether. The organic extract was dried over magnesium sulfate, filtered, and vacuum evaporated to an oily solid; 568 mg. (57%). Trituration of this residue with methanol then hexane and fractional crystallization from chloroform afforded pure title compound: 44 mg. (4%), mp 180°-183°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7].S([N:23]=[N+:24]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH3:3][O:4][P:5]([C:9](=[N+:23]=[N-:24])[C:10](=[O:12])[CH3:11])(=[O:8])[O:6][CH3:7]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COP(=O)(CC(C)=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a suspension of NaH (60% in mineral oil, 0.83 g, 20.8 mmols) in THF (50 ml) was added dropwise at 0 C (2-oxo-propyl)-phosphonic acid dimethyl ester (3.1 g, 18.7 mmols) in THF (50 ml), and the solution was stirred at 0 C for one hour. Tosyl azide (4 g, 20 mmols) was added in one portion, stirred at 0 C for 10 minutes, filtered through Celite and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate to yield the title compound (2.9 g, 81%) as oil. (Eur. J. Org. Chem. 2003, 821-832.)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([Cl:16])=[O:13])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-quinolinecarboxylic acid (Aldrich, 0.25 g, 1.4 mmol) in 5 mL of thionyl chloride was warmed to reflux and allowed to stir for 1 hour. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. This material was dissolved in 10 mL toluene and concentrated under reduced pressure (3×) to afford the title compound.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:23]=2[Cl:22])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccccc2Cl)nc1-c1cccc([N+](=O)[O-])c1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.72 g), 2-chloro-3-nitrobenzonitrile (1.00 g), anhydrous aluminum chloride (0.70 g) and o-dichlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.12 g of desired compound (melting point: 124.0°-125.0° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][SH:18])=[CH:13][CH:12]=1.CC[O-].[Na+]>C(O)C>[CH2:17]([S:18][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1nc(Cl)nc(C)c1Br
Reactant: SCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(SCc2ccccc2)nc(C)c1Br
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 94 %

Procedure:
2-Chloro-4,6-dimethyl-5-bromopyrimidine (10 mmol) was added to a solution of benzylthiol (11 mmol) and 0.138 M NaOEt in ethanol (80 ml). The mixture was stirred at room temperature for 70 min and then heated under reflux for 40 min. The solvent was then distilled off, the residue extracted with chloroform (50 ml), the chloroform solution washed with 2 M NaOH and the dried (MgSO4) solution evaporated to leave the sulfide which was purified by distillation; yield 94%, b.p. 232°-234° C./15 mmHg. 1H NMR (Cl3CF): δ2.50 (Me-4, Me-6), 4.26 (CH2), 7.20 (Ph).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]([NH:8][C:9]2[C:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)=O)[CH2:3][CH2:2]1.C(O)CO>O.[OH-].[Na+]>[CH:1]1([NH:4][C:5]([C:6]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[O:24])[CH2:3][CH2:2]1
Reactant: Cc1ccc(Nc2ncccc2NC(=O)C(=O)NC2CC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(-n2c(C(=O)NC3CC3)nc3cccnc32)cc1F
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of N-cyclopropyl-N′-{2-[(3-fluoro-4-methylphenyl)amino]pyridin-3-yl}ethanediamide (C3) (from the preceding step, 8.86 g, ≦16.6 mmol) and ethane-1,2-diol (27 mL) was stirred at 200° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and aqueous sodium hydroxide solution (1 M, 100 mL), then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 5% to 50% ethyl acetate in heptane) was followed by recrystallization from 3:1 toluene/heptane, to afford the product as a solid. Yield: 2.52 g, 8.12 mmol, 49% over three steps. LCMS m/z 311.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.7, 1.5 Hz, 1H), 8.13 (dd, J=8.1, 1.5 Hz, 1H), 7.68 (br s, 1H), 7.37 (dd, J=8.1, 4.7 Hz, 1H), 7.34-7.40 (m, 1H), 7.10-7.15 (m, 2H), 2.83-2.90 (m, 1H), 2.37 (br d, J=2 Hz, 3H), 0.83-0.89 (m, 2H), 0.67-0.72 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:17]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[Cs+]>CN(C=O)C>[C:11]1([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][O:21][C:18](=[O:20])[CH3:19])=[CH:17][C:7]=3[N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: BrCc1ccc2oc(-c3ccccc3)nc2c1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc2oc(-c3ccccc3)nc2c1
Yield: 101.2 %

Procedure:
5-Bromomethyl-2-phenylbenzoxazole 56 (1.0 g, 3.4 mmol) and cesium acetate (1.33 g, 6.94 mmol) were stirred together in DMF(25 ml) under an atmosphere of N2 overnight. The DMF was evaporated under high vacuum and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer was separated then washed and dried. Evaporation of the solvent yielded 920 mg of acetic acid 2-phenylbenzoxazol-5-ylmethyl ester 57.
Reaction SMILES: [CH2:1]([C:4]1([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][C:8](=[O:11])[O:7][C:5]1=[O:6])[CH2:2][CH3:3].P([O-])([O-])([O-])=[O:16]>C1COCC1>[CH2:1]([C:4]([CH2:10][CH2:9][C:8]([OH:7])=[O:11])([CH2:12][CH2:13][CH3:14])[C:5]([OH:16])=[O:6])[CH2:2][CH3:3]
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCC1(CCC)CCC(=O)OC1=O
Solvent: C1CCOC1
Product: CCCC(CCC)(CCC(=O)O)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of BSA (300 mg, 5×10-4 mmole) in 20 ml of phosphate buffer was added the hapten, 2,2-dipropylglutaric anhydride as prepared in Example 5 (55 mg, 0.25 mmole in 200 ml THF) in 4 μl portions over an hour. The resulting clear solution was stirred at 4° overnight, after which it was dialyzed in 7×2 liter of water adjusted to pH8 with phosphate buffer, followed by one time with deionized water. The dialysis took 5 days. Lyophilization gave 320 mg of conjugate having a hapten number of 40 as estimated by the amino group precipitation method.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OCC)=[O:19].[F:23][C:24]([F:33])([F:32])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[F:23][C:24]([F:32])([F:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=3)[S:5][C:4]=2[CH2:18][OH:19])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccc(C(F)(F)F)cc1

Procedure:
Prepared from intermediate 43 and 4-(trifluoromethyl)phenol
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=O)[N:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:33].O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]2[C:11](=[O:12])[NH:33][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)=[CH:16][N:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)c2ccc(C(C)(C)C)cc2)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(C(C)(C)C)cc3)cn2n1
Temperature: 25 °C

Procedure:
A solution of 1.04 g (2.71 mmol) 1-[2-(4-tert-butyl-phenyl)-2-oxo-ethyl]-1H-pyrazole-3,5-dicarboxylic acid diethyl ester and 2.08 g (27.1 mmol) ammonium acetate in 20 ml acetic acid is stirred for 44 hours at 110° C. The reaction mixture is cooled to room temperature and excess water is added. The resulting precipitate is filtered off, and washed with water. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent to give 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester as colourless crystals; HPLC/MS 2.41 (A), [M+H] 340.
Reaction SMILES: C(O)(=O)C.[CH:5]1([CH:8]=O)[CH2:7][CH2:6]1.[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=1.[BH4-].[Na+]>ClCCl>[Br:18][C:14]1[CH:15]=[C:16]([NH:17][CH2:8][CH:5]2[CH2:7][CH2:6]2)[C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ncc(Br)cc1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic acid (304 μl) and cyclopropanecarbaldehyde (406 μl) were added to a solution of 2,3-diamino-5-bromopyridine (1000 mg) in dichloromethane (25 ml) at room temperature, followed by stirring for 1 hour. Sodium tetrahydroborate (604 mg) was added to the reaction solution under ice-cooling, and the mixture was stirred with warming to room temperature for 22 hours. The reaction solution was extracted by adding a saturated aqueous sodium bicarbonate solution and dichloromethane. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (286 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:23][C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-nitrobenzhydrazide (2.16 g, 11.92 mmol) in pyridine (40 ml) cooled to 0° C. in an ice bath is added dropwise p-toluoyl chloride (1.94 g, 11.92 mmol). The mixture is allowed to warm to room temperature and stirred for 12 hours. The mixture is quenched with 350 mL of water and stirred for thirty minutes. The precipitate is filtered and dried in a vacuum oven :o yield 1-[(4-methyl)benzoyl]-2-(3-nitrobenzoyl)hydrazine as a pale yellow solid. (2.94 g, 82%).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:59]=[CH:58][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)[C:48](=[O:49])[NH:47][C:46](=[O:50])[NH:45][C:44]3=[O:51])=[O:40])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[N:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH:66]=O)[CH:61]=1>>[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:53][CH2:54][N:55]([CH2:66][C:62]5[CH:61]=[N:60][CH:65]=[CH:64][CH:63]=5)[CH2:56][CH2:57]4)[C:44](=[O:51])[NH:45][C:46](=[O:50])[NH:47][C:48]3=[O:49])=[O:40])=[CH:58][CH:59]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=Cc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(N4CCN(Cc5cccnc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 51 %

Procedure:
Following the procedure analogous to that used in reaction (9), the compound from Example 8 was reacted with 3-pyridine-carboxaldehyde for 2 days to provide the title compound (7.6 mg, 51%). MS found: (M+H)+=608.4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][C@H:22]3[CH2:24][C:25]([CH3:27])([CH3:26])[C@@H:19]2[C:20](=[O:28])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][C@H:22]3[CH2:24][C:25]([CH3:26])([CH3:27])[C@@H:19]2[C:20](=[O:28])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(OCc4ccccc4)cc3)[C@H]1C(=O)O2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(O)cc3)[C@H]1C(=O)O2
Yield: 82.9 %

Procedure:
A mixture of (1R,4R)-5-(4-benzyloxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVII, 3.7 g, 9.3 mmol), 10% palladium on charcoal (0.8 g) and 470 ml of 1:1 ethyl acetate-methanol was stirred for about 1.5 hours under about 50 psi of hydrogen gas. The mixture was filtered through a pad of Celite®. Concentration of the filtrate afforded 2.4 g (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVIII) as a colorless solid.