Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:29])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][NH2:23])=[N:20][C:19]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[N:18]1.[Cl:30][CH2:31][C:32](Cl)=[O:33].CN(C)C=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:29])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][NH:23][C:32](=[O:33])[CH2:31][Cl:30])=[N:20][C:19]([C:24](=[O:28])[N:25]([CH3:26])[CH3:27])=[N:18]1
Reactant: O=C(Cl)CCl
Reactant: CN(C)C(=O)c1nc(CN)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nc(CNC(=O)CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Yield: 1084.6 %

Procedure:
A mixture of 2',5-dichloro-2-(3-dimethylcarbamoyl-5-carbobenzoxyaminomethyl-1,2,4-triazol- 1-yl)benzophenone (3.6 g) and 30% hydrogen bromide-acetic acid (9 ml) is stirred at room temperature for 2 hours. The reaction mixture is mixed with ether, and the precipitate is isolated by decantation and washed thrice with ether, whereby 2',5-dichloro-2-(3-dimethylcarbamoyl-5-aminomethyl-1,2,4-triazol- 1-yl)-benzophenone hydrobromide is obtained. This hydrobromide (1.2 g) is added to a solution of chloroacetyl chloride (1.2 g) in benzene (40 ml) to give a solution, which is mixed with dimethylformamide (20 ml). The resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is mixed with ethyl acetate and neutralized with aqueous sodium bicarbonate. The organic layer is separated, washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is treated with ethanol/n-hexane to give 2',5-dichloro-2-[3-dimethylcarbamoyl-5-(2-chloroacetylamino)methyl-1,2,4-triazol- 1-yl]-benzophenone (12.9 g), which is recrystallized from ethyl acetate to give colorless needles melting at 80°-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=O)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.N1C=CC=CC=1.O>C(#N)C>[Cl:22][C:10]1[O:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 4-(4-chlorophenyl)-2-oxo-4-oxazoline-5-propionate (823.7 g) and phosphorus oxychloride (1090 mL) was added pyridine (235.5 mL) and the mixture was stirred at 90° C. for 8 h and allowed to stand overnight at room temperature. A solution obtained by diluting the obtained mixture with acetonitrile (2471 mL) was added dropwise to water (8237 mL) at not higher than 35° C. Then water (4119 mL) was added and the precipitated crystals were collected by filtration to give the title compound (805.4 g, yield: 91.7%).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].Cl[C:18]([O:20][CH3:21])=[O:19].O>O1CCCC1>[Br:10][C:4]1[N:3]([C:18]([O:20][CH3:21])=[O:19])[C:2]([Br:1])=[C:6]([C:7]#[N:8])[C:5]=1[Br:9]
Reactant: COC(=O)Cl
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)n1c(Br)c(Br)c(C#N)c1Br
Reaction time: 0.33 h

Procedure:
A solution of 2,4,5-tribromopyrrole-3-carbonitrile (3.0 g, 0,091 mo1) in tetrahydrofuran is treated portionwise with potassiumt-butoxide (1,33 g, 0.012 mol) at room temperature, stirred for 20 minutes, treated dropwise with a solution of methyl chloroformate (1,29 g, 0.014 mol) in tetrahydrofuran, stirred for 2 1/2 days, poured into water and extracted with ether. The combined ether extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown solid residue. The residue is recrystallized from ethyl acetate/hexanes to afford the title compound as a tan solid, 1.4 g (39.5%) mp 119.5° to 122.0° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([OH:35])=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([O:35][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.58 g), methyl 2-(5-bromo-2-hydroxyphenyl)acetate (3.0 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 0.54 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (4.46 g, 70%) of methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+](=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N-].[OH-].[Na+]>C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: OCCc1ccc(Cc2cccnc2)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COCCc1ccc(Cc2cccnc2)cc1
Yield: 15.7 %

Procedure:
In 10 ml of methylene chloride was dissolved 1.0 g of 2-[4-(pyridin-3-ylmethyl)phenyl]ethanol, and 980 mg of p-toluene sulfonic acid monohydrate was added thereto with ice-cooling. To the resulting solution was added 2.7 g of ethyl diazoacetate with ice-cooling, after which 700 mg of boron trifluoridediethyl ether complex was dropped into the solution. The resulting mixture was subjected to reaction at the same temperature for one hour. Subsequently, 20 ml of water and 20 ml of methylene chloride were added to the reaction mixture, and the pH thereof was adjusted to 8 with 1N aqueous sodium hydroxide solution, after which the organic layer was separated, washed successively with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluent: toluene:ethyl acetate (1:1 by volume)], to obtain 220 mg (yield 15.7%) of oily ethyl 2-[4-(pyridin-3-ylmethyl)phenyl]ethyloxyacetate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[N:7][CH:8]=1.COC(OC)C1N=CC(NC)=CC=1.[CH3:24][C@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:24][C@H:25]1[CH2:30][N:29]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][CH3:1])=[CH:8][N:7]=2)[CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CNc1ccc(C=O)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNc1ccc(C(OC)OC)nc1
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(methylamino)-2-pyridinecarbaldehyde and 6-[bis(methyloxy)methyl]-N-methyl-3-pyridinamine (D60) (0.622 g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.910 g, 4.552 mmol) and triethylamine (0.418 g, 4.139 mmol) in 1,2-DCE (40 mL) was stirred at room temperature overnight. Sodium tri(acetoxy)borohydride (1.14 g, 5.38 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with saturated aq. NaHCO3 solution and water. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-100% EtOAc/petroleum ether gave the title compound as a yellow/brown oil (0.542 g). δH (CDCl3, 400 MHz) 7.96 (1H, d), 7.23 (1H, d), 6.88 (1H, dd), 4.17 (1H, br.s), 3.80 (2H, d), 3.58 (1H, d), 3.45 (1H, d), 3.12 (1H, td), 2.86 (3H, s), 2.76 (1H, m), 2.58 (1H, m), 2.18 (1H, dd), 2.07 (1H, m), 1.45 (9H, s), 1.23 (3H, d). MS (ES): MH+ 321.4
Reaction SMILES: C[O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:14](=[O:26])[O:13][N:12]=2)=[N:8][O:9][N:10]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.O>[OH:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[C:14](=[O:26])[O:13][N:12]=2)=[N:8][O:9][N:10]=1
Reactant: COCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1onc(-c2nonc2NCCO)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.8 %

Procedure:
In a round bottom flask under nitrogen atmosphere, 3-{4-[(2-methoxyethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one (1.3 g, 3.6 mmol) was stirred in dichloromethane (11 mL). The temperature was brought to −78° C. and a solution of 1.0 M boron tribromide in dichloromethane (7.9 mL, 7.9 mmol) was added dropwise over 15 minutes. The reaction was warmed to room temperature over 45 minutes and continued to stir at room temperature for an additional 45 minutes. The reaction was cooled to 0° C. and a saturated solution of sodium bicarbonate in water (25 mL) was added dropwise over 15 minutes. After warming to room temperature, ethyl acetate (10 mL) and water (10 mL) were added to the flask. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2×20 mL). After drying the combined organic layers over sodium sulfate, the solvent was removed in vacuo to give the desired product (1.0 g, 81%). LCMS calculated for C13H11F3N5O4 (M+H)+: m/z=358.0. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.93 (t, J=8.2 Hz, 2H), 7.79 (t, J=8.2 Hz, 1H), 6.35 (t, J=5.7 Hz, 1H), 4.86 (br s, 1H), 3.55 (t, J=6.0 Hz, 2H), 3.28 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][CH:13]1[CH2:16][CH2:15][CH2:14]1.O1CCOCC1.CO.[Li+].[OH-]>CO.C(Cl)Cl.O>[Cl:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([O:12][CH:13]2[CH2:14][CH2:15][CH2:16]2)=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(Cl)cc(C)c1OC1CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)O)c1OC1CCC1
Reaction time: 39 h
Yield: 98.7 %

Procedure:
A 100 mL flask containing 5-chloro-2-cyclobutoxy-3-methyl-benzoic acid methyl ester (0.57 g, 2.23 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by the LiOH (237 mg, 5.65 mmol). After 39 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜6 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated by pumping to constant weight to give 0.53 g of white solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[CH:29][S:28][CH:27]=3)=[CH:22][C:20]=2[CH:21]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>CO.O>[S:28]1[CH:29]=[CH:30][C:26]([C:23]2[CH:24]=[CH:25][C:19]3[O:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:3]([OH:31])=[O:2])=[O:14])=[CH:21][C:20]=3[CH:22]=2)=[CH:27]1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccsc3)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1cc2cc(-c3ccsc3)ccc2o1
Temperature: 50 °C
Yield: 65.9 %

Procedure:
A solution of (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 23 (0.23 g, 0.54 mmole) in methanol (10 ml) was treated with a solution of lithium hydroxide monohydrate (25 mg, 0.59 mmole) in water (1 ml) and heated to 50° C. for 4 hrs, cooled, acidified with 1M HCl, evaporated, partitioned between ethyl acetate and 1M HCl, separated, washed, dried, and evaporated. The residue was crystallized giving about 0.15 g of (R)-2-(5-thiophen-3-yl-benzofuran-2-ylmethoxycarbonylamino)-3-phenylpropionic acid 24, mp. 169-170° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1.[F:29][C:30]([F:36])([F:35])[CH2:31][C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:29][C:30]([F:36])([F:35])[CH2:31][C:32]([NH:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][CH:8]=1)=[O:33]
Reactant: O=C(O)CC(F)(F)F
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(CC(F)(F)F)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 (8 mL) were added 3,3,3-trifluoropropanoic acid (0.032 g, 0.24 mmol), HOBt.H2O (52 mg, 0.33 mmol), EDC.HCl (0.065 g, 0.33 mmol) and DIEA (0.044 g, 0.45 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc (3×30 mL). The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as a gummy material (60 mg, 50%): mp 151-153° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (br s, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m, 2H); ESIMS m/z 554.04 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+]>CO.O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[OH:23])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccccc1
Yield: 83.6 %

Procedure:
A solution of 100 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanone and 23 mg of sodium borohydride in 5 ml of methanol was stirred at rt for 17 h. The mixture was diluted with 4 ml of water and extracted four times with diethyl ether. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum spirit 40°-60° C. for the elution to give 84 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanol as a colourless gum. Mass spectrum (EI) m/z 440 [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(O[I:16](OC(=O)C)([O-])(=O)=O)(=O)C.C([N+](CC)(CC)CC)C>ClCCl>[OH:1][C:2]1[C:9]([I:16])=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CC(=O)O[I+2]([O-])([O-])([O-])OC(C)=O
Agent: CC[N+](CC)(CC)CC
Solvent: ClCCl
Product: COc1cc(I)c(O)c(C=O)c1
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To a solution of 2-hydroxy-5-methoxy-benzaldehyde (15.97 g, 104.9 mmole) in 375 mL dichloromethane at −15° C. was added tetraethylammonium diacetoxyiodate (48.06 g, 128.1 mmole) over 15 minutes. After stirring overnight, an additional amount of tetraethylammonium diacetoxyiodate (46.93 g, 125.1 mmole) was added over 15 minutes. The reaction was stirred for an additional 12 hours, concentrated, and added to 2N HCl. The mixture was extracted into ethyl acetate and the combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated in vacuo and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 3.47 g (11.9%) of iodide as a yellow solid: Mp=103-105° C.; 1H NMR (DMSO-d6) δ 11.3 (s, 1 H), 9.73 (s, 1 H), 7.60 (d, 1 H, J=3.0 Hz,), 7.07 (d, 1 H, J=3.1 Hz), 3.83 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C)C=O>[NH2:21][C:18]1[S:19][CH:20]=[C:16]([CH2:15][O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[N:17]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1OCc1csc(N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (552 mg), 4-(chloromethyl)thiazol-2-amine hydrochloric acid (600 mg) and Cs2CO3 (2.64 g) in 15 mL N,N-dimethylformamide was stirred at room temperature for 24 hours. Water was added and the mixture was extracted with ethyl acetate (2×), washed with water (2×) and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel using 10-50% ethyl acetate in hexanes as eluent.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Nc1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
DIPEA (1.631 mL, 9.36 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.389 g, 6.24 mmol) and 4-(piperidin-4-yl)aniline (1.21 g, 6.86 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and purified by flash chromatography on silica gel, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to give 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]aniline (1.910 g, 84%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl.Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>O>[N:32]1([CH2:31][CH2:30][CH2:29][O:14][N:13]=[C:8]2[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]2=3)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: ClCCCN1CCOCC1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cl
Agent: [H-]
Solvent: O
Product: Cc1nc(N)nc2c1C(=NOCCCN1CCOCC1)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (100 mg, 0.290 mmol), 4-(3-chloro-propyl)-morpholine hydrochloride (70 mg, 0.348 mmol) and sodium hydride (60% dispersion in oil) (37 mg, 0.928 mmol) following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88) except after addition of water the solvent was removed under reduced pressure. The crude material was taken up in EtOAc (20 ml) and the resulting solution was filtered. The solvent was removed under reduced pressure and the title compound was purified by column chromatography eluting with dichloromethane/methanol (97/3).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]([CH:15]=2)[C:11](OC)=[O:12])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]([CH2:11][OH:12])[CH:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cc(-n2ccnc2)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2ccnc2)cc1CO
Temperature: 24 °C
Reaction time: 18 h

Procedure:
5-(1H-Imidazol-1-yl)-2-methoxybenzoic acid, methyl ester (2 g, 8.6 mmol) was cooled to 0C in anhydrous THF under N2 and LiAlH4 was added. The reaction mixture stirred for 18 h at 24° C,. and water (0.7 ml) followed 15% sodium hydroxide solution (0.7 ml) and water (0.7 ml) was sequentially added dropwise. The resultant suspension was filtered and concentrated to give 1.3 g (74%); 1H NMR (300 MHz, DMSO-d6) δ 3.81(3H, s), 4.52 (2H, d, J=4.3 Hz), 5.18 (1H, br. s), 7.04 -7.06 (2H, m), 7.43 (1H, dd, J=8.7 Hz, 2.8 Hz), 7.52 (1H, d, J=2.8 Hz) 7.58 (1H, s), 8.07 (1H, s); MS(DCl)m/z: 205 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH:11][C:12]=2[Cl:14])[C:7](=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:20]([NH:23]C1C=CC=C2C=1C(=O)CCC2)(=[O:22])[CH3:21]>>[C:1]([N:4]1[C:13]2[C:8](=[C:9]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH:11][C:12]=2[Cl:14])[C:7](=[O:19])[CH:6]([NH:23][C:20](=[O:22])[CH3:21])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCN2C(C)=O
Reactant: CC(=O)Nc1cccc2c1C(=O)CCC2
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(NC(C)=O)CN2C(C)=O

Procedure:
The reaction was carried out in the same manner as in Example b 1-(2), except that 1.4 gm of the compound prepared in (1) above was used instead of 8-acetylamino-1-tetralone of Example 1-(2). The reaction mixture obtained by the post-treatment was further reacted in the same manner as in Example 1-(3) and post-treated to produce 0.62 gm of the title compound.