Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](C(O)=O)=[CH:13][N:12]=[C:11]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:25](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([NH2:25])=[CH:13][N:12]=[C:11]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 66 °C
Yield: 40 %

Procedure:
4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 2-e, (200 mg, 0.68 mmol) was dissolved in THF (20 ml) and treated with Et3N (204 mg, 2.02 mmol) and DPPA (204 mg, 0.74 mmol). The mixture was heated at 66° C. for 12 hours. Then water was added and the resulting mixture was continued to stir at reflux for 2 h. After that the mixture was concentrated under vacuum. The residue was diluted with aq. K2CO3 followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel column with the eluent of dichloromethane/methanol=50/1 (Rf=0.7) to provide compound 2-f (72 mg, 40%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([S:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:24])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1CCCC2Sc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccnc2c1CCCC2S(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
A solution of the product of Step 4 (10.0 g, 39.2 mmol) in dichloromethane (200 ml) was treated portionwise with 86% 3-chloroperoxybenzoic acid (8.0 g, 40 mmol) at <10°, stirred for 30 min, washed with 0.1N-NaOH, dried (Na2SO4), and evaporated in vacuo to give the crude product (10.8 g) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:3]2[C:2]([O:1][CH2:19][C:20]3[C:21]([F:28])=[CH:22][CH:23]=[C:24]([F:27])[C:25]=3[F:26])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]2[C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Fc1ccc(F)c(CBr)c1F
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)ccc(F)c3F)cc(C)cn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
3.00 g (12.81 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 239A, 3.27 g (14.1 mmol) of 2-(bromomethyl)-1,3,4-trifluorobenzene and 9.18 g (28.17 mmol) of caesium carbonate were initially charged in 183 ml of dry DMF and heated for 30 min in an oil bath warmed to 60° C. About 1.8 l of water were then added, and the mixture was stirred for 30 min. The solid was filtered off, washed with water and dried under reduced pressure. This gave 5.07 g of the title compound (99% of theory; purity about 96%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(OC(=O)[NH:41][CH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([N:51]=[C:52]([NH:54][CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)[CH3:53])[CH:49]=2)[CH2:44][CH2:43]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:63][C:60]1[CH:59]=[CH:58][C:57]([CH2:56][CH2:55][NH:54][C:52](=[N:51][C:48]2[CH:49]=[C:50]3[C:45]([CH2:44][CH2:43][C@H:42]3[NH:41][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:19])[F:18])=[CH:14][CH:13]=3)=[O:17])=[CH:46][CH:47]=2)[CH3:53])=[CH:62][CH:61]=1
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: CC(=Nc1ccc2c(c1)C(NC(=O)OC(C)(C)C)CC2)NCCc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=Nc1ccc2c(c1)[C@H](NC(=O)c1ccc(-c3ccccc3C(F)(F)F)cc1)CC2)NCCc1ccc(F)cc1
Yield: 46.8 %

Procedure:
Stir a mixture of 2′-trifluoromethylbiphenyl-4-carboxylic acid (100 mg, 0.376 mmol), N-hydroxysuccinimmide (43 mg, 0.376 mmol) and DCC (77 mg, 0.376 mmol) in 15 mL of methylene chloride at rt for 2 h. Combine (6-(1-((4-fluorobenzyl)methylamino)ethylideneamino)indan-1-yl)carbamic acid tert-butyl ester (129 mg. 0.313 mmol) with TFA (2 mL) at 0° C. and stir for 2 hr. Evaporate TFA under reduced pressure. Dissolve the residue in methylene chloride and evaporate to dryness; repeat this three times. Add 5 mL of methylene chloride and 1 mL of triethylamine. Add this resulting solution to the above mixture and stir at rt for 12 h. Pour the mixture into methylene chloride, wash with water, dry with Na2SO4, and concentrate. Purify the residue by column chromatography (silica gel, 3% MeOH in CH2Cl2) to give 82 mg of the title compound as a white solid (47% yield).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:7][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1cccc(C(O)COc2ccc(C=O)cc2)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(C(O)COc2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 57.5 %

Procedure:
To a stirring solution of 4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzaldehyde (1.76 g, 6.46 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.83 g, 7.11 mmol) and piperidine (0.70 mL, 7.11 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with water (pH adjusted to ca. 5-6 with HOAc), brine, dried (Na2SO4), filtered and adsorbed onto silica gel. After chromatography with 20-30% EtOAc/DCM, the fractions containing compound were combined and evaporated in vacuo to give 1.38 g (58%) of the title compound as a yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: O=[C:2]1[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][C:13](=O)[N:12]2[CH2:21][CH2:22][S:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][N:3]1[CH2:4][CH2:5][S:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11]2.[H]1[BH2][H][BH2]1>O1CCCC1>[N:3]12[CH2:4][CH2:5][S:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][N:12]([CH2:21][CH2:22][S:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28]1)[CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:2]2
Reactant: O=C1COCCOCC(=O)N2CCSCCSCCN1CCSCCSCC2
Solvent: C1CCOC1
Product: C1COCCN2CCSCCSCCN(CCO1)CCSCCSCC2
Yield: 95 %

Procedure:
A solution of 0.6 g. of the bicyclic diamide obtained in Example 34 in 10 ml. tetrahydrofuran is slowly added to 10 ml. of the freshly prepared B2H6 solution (1.5 M) under nitrogen atmosphere and at a temperature of 0° C. The mixture is refluxed for two hours. The excess reagent is destroyed by adding 5 ml. of water and the solution is evaporated on a rotatory evaporator under vacuum. The solid residue is treated with 50 ml. 6 N hydrochloric acid under reflux for two hours. The mixture is evaporated to dryness under vacuum on a rotatory evaporator. The residue is treated with a solution of tetraethylammonium hydroxide until a basic reaction is obtained. The mixture containing a precpitate, is extracted several times with chloroform. The solutions are filtered through alumina and evaporated to dryness leaving the title compound as a crystalline residue.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH2:6]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1C=CC=CC=1>[CH3:1][N:2]([CH3:20])[C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH2:6]1)=[S:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(C)C(=O)C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Solvent: c1ccccc1
Product: CN(C)C(=S)C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 137.4 %

Procedure:
A mixture of 0.43 g of N,N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide, 0.33 g of Lawesson's reagent, and 2 ml of benzene was heated under reflux for 30 minutes. The reaction product was purified by silica gel column chromatography (CH2Cl2) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 0.33 g of N,N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8](OCC)=[O:9])=[C:4]([CH:22]=O)[C:3]=1[F:24].C([BH3-])#N.[Na+].Cl.[C:30]([N:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1)(=[O:32])[CH3:31]>CO>[C:30]([N:33]1[CH2:36][CH:35]([N:37]2[CH2:22][C:4]3[C:3]([F:24])=[C:2]([Cl:1])[CH:15]=[C:14]([C:16]4([CH3:21])[O:20][CH2:19][CH2:18][O:17]4)[C:5]=3[O:6][CH:7]([CH3:13])[C:8]2=[O:9])[CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CC(N)C1
Reactant: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CC(N2Cc3c(F)c(Cl)cc(C4(C)OCCO4)c3OC(C)C2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A solution of ethyl 2-[4-chloro-3-fluoro-2-formyl-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate (392 mg, 1.09 mmol) in methanol (21 mL) was treated with sodium cyanoborohydride (171 mg, 2.72 mmol) followed by 1-acetylazetidin-3-amine hydrochloride (360 mg, 2.39 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with acetic acid (200 μL) and concentrated in vacuo. The residue was diluted with toluene (60 mL) and heated at 110° C. for 2 h. The solvent was concentrated in vacuo, and the residue was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (142 mg, 32%) as a mixture of enantiomers. LCMS calculated for C19H23ClFN2O5(M+H)+: m/z=413.1; found: 413.1.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[F:25])#[N:17].[C:26]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:30])/[CH:27]=[CH:28]/[CH3:29]>CN(C)C1C=CN=CC=1.ClCCl>[C:26]([O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:25])[CH:20]=2)=[O:37])=[CH:39][CH:40]=1)(=[O:30])/[CH:27]=[CH:28]/[CH3:29]
Reactant: N#Cc1ccc(O)cc1F
Reactant: C/C=C/C(=O)Oc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/C(=O)Oc1ccc(C(=O)Oc2ccc(C#N)c(F)c2)cc1
Reaction time: 8 h
Yield: 105.6 %

Procedure:
2.6 g of N,N'-dicyclohexylcarbodiimide were added while stirring within 5 minutes to a solution of 1.2 g of 4-cyano-3-fluorophenol, 1.2 g of 4-[(E)-but-2-enoyloxy]benzoic acid and 0.1 g of 4-(dimethylamino)pyridine in 50 ml of dichloromethane. The reaction mixture was stirred overnight, then filtered. The filtrate was washed with saturated sodium bicarbonate solution and with water and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) and two-fold recrystallization of the fractions which were pure according to thin-layer chromatography gave 2.0 g of 4-cyano-3-fluorophenyl 4-[(E)-but-2-enoyloxy]benzoate. M.p. (C-N) 125° C. and cl.p. (N-I) 195° C.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH2:10]O.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:26]([CH2:10][C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1)=[N+:27]=[N-:28]
Reactant: OCc1cc2cnccc2s1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cc2cnccc2s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.6 %

Procedure:
To a flame-dried round-bottomed flask containing thieno[3,2-c]pyridin-2-ylmethanol (D-3) (3.2 g, 19.4 mmol) was added DPPA (8 g, 6.26 mL, 29.1 mmol) in THF (50 mL). The reaction mixture was stirred for 5 mins and cooled to 0° C., followed by adding DBU (4.43 g, 4 mL, 29.1 mmol) via syringe. The mixture was allowed to stir at reflux overnight. The reaction was then partitioned between water and ethyl ether. The aqueous layer was extracted with ethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by chromatography to afford the product (3.27 g). MS (m/z): 191 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[CH2:14]Cl)[CH2:2][CH2:3][CH3:4].[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:18]([O:17][P:16]([CH2:14][C:7]1[CH:8]=[C:9]([CH:10]=[O:11])[CH:12]=[CH:13][C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:23])[O:20][CH2:21][CH3:22])[CH3:19]
Reactant: CCOP(OCC)OCC
Reactant: CCCCOc1ccc(C=O)cc1CCl
Product: CCCCOc1ccc(C=O)cc1CP(=O)(OCC)OCC

Procedure:
4-Butoxy-3-chloromethylbenzaldehyde and triethyl phosphite in a 1:1 ratio were heated until no more gas evolved and the reaction mixture had turned light orange. The reaction mixture was then vacuum distilled to give the desired product. bp 188° C. at 1.4 mm Hg.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:11])=[N:5][C:6]([Cl:10])=[CH:7][C:8]=1[CH3:9])#[N:2].S(=O)(=O)(O)[OH:13]>>[Cl:11][C:4]1[C:3]([C:1]([NH2:2])=[O:13])=[C:8]([CH3:9])[CH:7]=[C:6]([Cl:10])[N:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Reactant: O=S(=O)(O)O
Product: Cc1cc(Cl)nc(Cl)c1C(N)=O
Reaction time: 0.5 h

Procedure:
3-Cyano-2,6-dichloro-4-methylpyridine (80g, 0.42 mole) was dissolved in concentrated sulfuric acid (440ml). The mixture was heated at 150° C.-170° C. with stirring for 30 minutes, cooled and poured on ice. The precipitate was filtered and washed with water. The wet filter cake was dissolved in methylene chloride, washed, neutralized with Na2Co3, dried over Na2SO4 (anhydrous), and concentrated until a white precipitate separated. Petroleum ether was added, the crystals were filtered and dried at room temperature overnight to give 83g (94%) of 2,6-dichloro-4-methyl-3-pyridinecarboxamide.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35]1([N:41]=[C:42]=[S:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:42](=[S:43])[NH:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: S=C=Nc1ccccc1
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=S)Nc1ccccc1)C3
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.5 %

Procedure:
A mixture of the compound obtained in Example 5A (1.0 g), phenyl isothiocyanate (0.31 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 14 hours, after which it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane-methanol (20:20:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-phenylthiocarbamoyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (1.03 g, 80%), which was then recrystallized from ethyl acetate-hexane to yield colorless crystals having a melting point of 104 to 106° C. ##STR51##
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.C.C[OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:28])=[N:9][N:8]=2)=[CH:24][CH:25]=1
Reactant: CO
Reactant: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Product: O=C(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C

Procedure:
Heating of a mixture of 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazine (Example 4 in WO 98/35958) and charcoal in boiling methanol for about 7 days in an open vessel leads to partial oxidation of the methylen-bridge of 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazine. After cooling to RT, unchanged 1-(4-chloranilino)-4-(4-pyridylmethyl)-phthalazine crystallizes out and can be filtered off. Chromatography (SiO2; dichloromethane/methanol 98:2) of the concentrated filtrate then leads to [4-(4-chloranilino)phthalazin-1-yl](pyridin-4-yl)ketone and rac. [4-(4-chloranilino)phthalazin-1-yl](pyridin-4-yl)methanol (see Expl. 78 in WO 98/35958). [4-(4-Chloranilino)phthalazin-1-yl](pyridin-4-yl)ketone: 1H NMR (DMSO-d6) δ9.88 (bs, 1H, HN), 8.79 (d, 2H, pyridine), 8.71 (d, 1H), 8.63 (d, 1H), 8.07 (m, 2H), 7.97 (d, 2H, chloranilino), 7.77 (d, 2H, pyridine), 7.45 (d, 2H, chloranilino); IR (KBr): 3287, 3139, 3066, 1667 (CO), 1620 cm−1; FAB MS (M+H)+=361. rac [4-(4-Chloranilino)phthalazin-1-yl](pyridin-4-yl)methanol: m.p. 197-197.5 dec; 1H NMR (DMSO-d6) δ9.32 (bs, 1H, HN), 8.57 (d, 1H), 8.49 (d, 2H, pyridine), 8.22 (d, 1 H), 8.00 (d, 2H, chloranilino), 7.93 (m, 1H), 7.84 (m, 1H), 7.41 (d, 2H, pyridine); 7.40 (d, 2H, chloranilino), 6.77 (d, 1H, HO), 6.30 (d, 1H, HC-OH); IR (KBr): 3386 (OH), 3122, 2852, 1619, 1600, 1521, 1493, 1406 cm−1; FAB MS (M+H)+=363.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)SC)#[N:2].O.[NH2:22][NH2:23]>C(O)C>[NH2:2][C:1]1[NH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[N:22][N:23]=1
Reactant: CSC(=NC#N)N1CCN(Cc2ccc(F)cc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1nnc(N2CCN(Cc3ccc(F)cc3)CC2)[nH]1

Procedure:
The entire portion (0.1 mole) of N-cyano-4-(p-fluorobenzyl)-1-piperazinecarboximidothioic acid, methyl ester, prepared as an oil (Example 27) was dissolved in 150 ml. of ethanol and 5.5 ml. (0.11 mole) of hydrazine hydrate were added. The mixture was refluxed for 6 hours and then evaporated to a solid residue which as crystallized from 200 ml. of ethanol, giving 21 g. of the desired product as colorless crystals, m.p. 213°-216° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)[CH:5]=1.C1COCC1.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]2)[CH:5]=1
Reactant: COC(=O)c1cccc(N2CCC3(CC2)OCCO3)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N2CCC(=O)CC2)c1
Yield: 84.9 %

Procedure:
A solution of methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate (3.85 g, 13.88 mmol) in 10% aqueous sulfuric acid (40 mL and THF (40 mL) was stirred at ambient temperature for 14 days. The reaction mixture was neutralized by cautious addition of NaHCO3 and simultaneously diluting with water. The aqueous mixture was extracted with EtOAc (2×75 mL) and the combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound as an oil (2.75 g, 85%) which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:13])=[N+:5]([O-:12])[CH:6]=[CH:7][C:8]=1[N+]([O-])=O)[CH3:2].C([Cl:17])(=O)C>>[Cl:17][C:8]1[CH:7]=[CH:6][N+:5]([O-:12])=[C:4]([CH3:13])[C:3]=1[CH2:1][CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1c([N+](=O)[O-])cc[n+]([O-])c1C
Product: CCc1c(Cl)cc[n+]([O-])c1C
Temperature: -15 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
First, 3-ethyl-2-methyl-4-nitropyridine 1-oxide (3.37 g, 18.5 mmol) was added to acetyl chloride (20 ml, 281 mmol) in a nitrogen atmosphere at −30° C. The mixture was stirred at −30 to 0° C. for 3 hours. After the reaction mixture was concentrated, the residue was partitioned by chloroform and a saturated aqueous sodium hydrogen carbonate solution. After insoluble substance was removed by filtration, the aqueous layer was extracted twice with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 100 g, elution solvent: heptane, heptane/ethyl acetate=50/50) to obtain the title compound (2.10 g, yield: 66.1%) as a yellow oil.
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=[CH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH2:5][CH2:4]1.[Br:24]Br>C(O)(=O)C>[BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=3[CH:12]([Br:1])[CH:13]([Br:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)[CH2:5][CH2:4]1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CN1CCC(=C2c3ccccc3C(Br)C(Br)c3ccccc32)CC1
Temperature: 25 °C

Procedure:
1-Methyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrobromide, 18.40 g. (0.05 mole) is dissolved with warming in 750 ml. of glacial acetic acid. This solution is cooled to room temperature and 8.0 g., 2.6 ml., (0.05 mole) of bromine dissolved in 75 ml. of glacial acetic acid is added dropwise with stirring. After completion of the addition the mixture is stirred overnight. The crystals are collected, washed with a small amount of cold glacial acetic acid, then with dry ether, and then dried for 2 hours in a vacuum oven at 70° to give 1-methyl-4-(10,11-dibromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrobromide. Recrystallization from acetonitrile gives an analytical sample, m.p. 185°-186°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:48])C(=O)C1.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Br:48])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: COc1cccc(OC)c1-c1ccc(CO)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(OC)c1-c1ccc(CBr)c([N+](=O)[O-])c1

Procedure:
To a solution of 1.8 g (6.23 mmol) of 4-(2′,6′-dimethoxyphenyl)-2-nitrobenzyl alcohol and 2.3 g (8.72 mmol) of Ph3P in CH2Cl2 (20 mL) at 0° C. was added 1.32 g (7.5 mmol) of NBS. The reaction mixture was stirred at 0° C. for 30 min at which time TLC analysis (eluted with 25% Et2O in hexanes) indicated that the starting material had been consumed. The reaction mixture was concentrated and the crude residue was purified by flash column chromatography on silica gel eluted with 50% Et2O in hexanes to give 4-(2′,6′-dimethoxyphenyl)-2-nitrobenzyl bromide as a pale yellow solid. Trituration with hexanes gave the product as a white solid.