Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([O:17]C)=[O:16])[O:8][C:4]=2[CH:3]=1.[OH-].[Li+]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([OH:17])=[O:16])[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccc(Br)cc2o1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCCN1c1nc2ccc(Br)cc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from methyl (2S)-1-(6-bromo-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate [see Preparation 5] and 1N aqueous lithium hydroxide solution, to afford (2S)-1-(6-bromo-1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid as a pink foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17]([O:19]CC)=[O:18])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][N:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1noc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 7.31 g (25 mmol) of 6,7-dihydro-4H-isoxazolo[4,5-c]pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-tert-butyl ester (E), 43 g (30 mmol) of lithium hydroxide and 75 mL of EtOH was stirred at RT for 12 h. The solvent was removed under a vacuum and the residue redissolved in a mixture of water/citric acid (pH=4) and ether. The organic phase was separated off, dried over magnesium sulfate and the solvent was removed under a vacuum. 6.65 g (99% of theoretical) of the desired product 6,7-dihydro-4H-isoxazolo[4,5-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester (F) were obtained in the form of a yellow oil which crystallised at RT.
Reaction SMILES: [NH2:1][C@@:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([Br:18])[N:12]=1)([CH3:10])[CH2:3][C@H:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]=[C:29]=S)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>CC#N>[Br:18][C:13]1[N:12]=[C:11]([C@:2]2([CH3:10])[CH2:3][C@H:4]([C:5]([F:6])([F:7])[F:8])[O:9][C:29]([NH:28][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:32][CH:31]=3)=[N:1]2)[C:16]([F:17])=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@](N)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(c2nc(Br)ccc2F)C[C@H](C(F)(F)F)OC(NC(=O)c2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4S)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1-trifluoropentan-2-ol (7f, 0.183 g, 0.553 mmol) in MeCN (3 mL) was added 4-nitrobenzoyl isothiocyanate (Matrix, 0.150 g, 0.719 mmol). The mixture was stirred at room temperature for 30 min. Additional 4-nitrobenzoyl isothiocyanate (30 mg) was added and the reaction was allowed to stir for additional 20 min. N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (Aldrich, 0.170 g, 0.884 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.241 mL, 1.382 mmol) was added and the reaction mixture was heated to 70° C. for 1 h. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated washed with brine, and dried over sodium sulfate. The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (0-60% EtOAc/hexanes) to obtain the title compound as an off-white solid. MS m/z=505/507 [M]+/[M+2]+. Calculated: 505.2
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)CCC.[N-:15]=[N+:16]=[N-:17].[Na+].C(O)(=O)C>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:17][N:16]=[N:15][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCO
Solvent: CCOCC
Product: Fc1ccccc1-c1nnn[nH]1
Temperature: 25 °C

Procedure:
The 5-(2-fluorophenyl)-1H-tetrazole starting material was prepared as follows. A 3-necked 500 ml round-bottom flask was charged with 2-fluorobenzonitrile (48.4 g, 0.4 mol), n-butanol (160 ml), NaN3 (34.3 g, 0.528 mol) and glacial acetic acid (31.7 g, 0.528 mol). The mixture was warmed to a mild reflux for 24 h under nitrogen behind a safety shield. After the mixture had cooled to room temperature, it was again charged with NaN3 (34.3 g, 0.528 mol) and glacial acetic acid (31.7 g, 0.528 mol). The mixture was warmed to a mild reflux for an additional 24 h under nitrogen, cooled and then diluted with diethyl ether (320 ml). This organic mixture was extracted with 2N NaOH (4×100 ml) and the combined ice-cold basic extracts were carefully acidified to pH 1 with concentrated hydrochloric acid. The product was isolated as a light gray solid (45.2 g, 68.9%) after drying under vacuum at 60° C., mp 160.5°-162° C. [lit. mp 160°-162° C.; George, E. F. and Riddell, W. D., U.S. Pat. No. 3,865,570 (Feb. 13, 1973)]. There was obtained a second crop of product (1.0 g, 1.5%). A 1.0 g sample of this material was crystallized from water to produce a white solid, mp 162.5°-163.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:26]=[CH:25][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[C:28]1(CCOCC)C(=O)NC(=O)NC1=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:26]=[CH:25][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:28])=[CH:20][CH:19]=4)=[CH:15][CH:14]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: Oc1ccc(Oc2ccc(-c3ccn(-c4ccc(Cl)cc4)n3)cc2)cc1
Product: COc1ccc(Oc2ccc(-c3ccn(-c4ccc(Cl)cc4)n3)cc2)cc1

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(4-Chloro-phenyl)-1H-pyrazol-3-yl]-phenoxy}-phenol and 5-bromo-5-(2-methoxyethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+ 547.1 (M+H)+, ESI− 545.3 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:34])([CH3:33])[CH2:9]2)=[O:5])C.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[C:16]([CH:11]3[C:10]([CH3:34])([CH3:33])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cc(F)cc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
A mixture of 2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.17 g, 0.37 mmol) in ethanol (3 mL) and tetrahydrofuran (5 mL), 30% sodium hydroxide in water (1 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.13 g, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C28H30FNO2 (M+H)+: 432.6, observed: 432.3;
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.Br[CH2:18][CH:19]([CH3:21])[CH3:20]>>[CH2:18]([S:12][C:8]1[C:7]([C:13]#[N:14])=[CH:6][C:5]2[C:4](=[O:15])[CH2:3][C:2]([CH3:16])([CH3:1])[CH2:11][C:10]=2[N:9]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Reactant: CC(C)CBr
Product: CC(C)CSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 42 %

Procedure:
In analogy to the procedure described in Example 1, 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 1-bromo-2-methylpropane to give the title compound in 42% yield.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:25]=[N:24][N:23]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH:22]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccccc1-c1cn[nH]c1
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)n1cc(-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-Nitrophenyl chloroformate (2.3 g, 11.5 mmol) and 4-(2-chlorophenyl)-1H-pyrazole (2.0 g, 11.0 mmol) are dissolved in 30 mL CH2Cl2 and cooled to 0° C. TEA (1.7 mL, 12.0 mmol) is added, and the reaction is allowed to warm to RT. After 30 min, additional 4-nitrophenyl chloroformate (0.25 g) and TEA are added. After 1 h, water is added. The mixture is extracted with CH2Cl2, dried (MgSO4), filtered and concentrated to give a solid. The solid is triturated with hexanes, filtered and dried to provide 1.7 g (45%) of the crude 4-nitrophenyl 4-(2-chlorophenyl)-1H-pyrazole-1-carboxylate.
Reaction SMILES: C1COCC1.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.[Cl:16][CH2:17][Si:18](Cl)([CH3:20])[CH3:19].C([Li])CCC>O.C(OCC)(=O)C>[Cl:16][CH2:17][Si:18]([CH3:20])([CH3:19])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc([Si](C)(C)CCl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
A mixture of 60 ml of THF, p-bromophenetole (9.7 gram) and chloromethyldimethylsilyl chloride (7.3 gram) was cooled in a dry ice/acetone bath. To the mixture was dropwise added 33 ml of 1.55M n-butyl lithium under an argon atmosphere. After stirring the mixture for additional 15 minutes at -78° C., the stirring was continued at room temperature for 30 minutes. The mixture was added with 6 ml of ethyl acetate and 30 ml of water, and extracted with ethyl ether. The ether extract was washed with saturated sodium chloride solution, dried, and concentrated. Distillation of the residue gave 5.5 gram of chloromethyldimethyl(4-ethoxyphenyl)silane. Physicochemical data of the product is listed in Table 3.
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1.[CH3:44][O:45][CH2:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>N1C=CC=CC=1.ClCCl>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:3]2[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:2]=2[NH:1][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][O:45][CH3:44])=[CH:13][CH:14]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)cc2N)cc1
Reactant: COCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCCC(=O)Nc1cc(C)ccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
The solution of 0.278 g of tert-butyl 3-(2-amino-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 0.046 ml of pyridine and 2.3 ml of dichloromethane is cooled to 0° C. and admixed slowly with 0.078 g of 4-methoxybutyryl chloride. The reaction mixture is concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.06 (1:1 EtOAc-heptane); Rt=5.86.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)(C(OC)=O)[C:12]([O:14]C)=[O:13])=[CH:4][C:3]=2[O:2]1.[OH-].[K+]>C(O)CCC.O>[CH2:28]1[O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][CH:11]([CH2:10][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[C:12]([OH:14])=[O:13])=[CH:22][C:23]=2[O:29]1
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)(Cc1ccc2c(c1)OCO2)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: O=C(O)C(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Yield: 55.2 %

Procedure:
A solution of 20.58 g (0.051 mol) of dimethyl bis-(3,4-methylenedioxyphenylmethyl)malonate in 50 mL of n-butanol was treated with a solution of 8.58 g (0.153 mol) of KOH in 50 mL H2O and heated at reflux overnight. The solvent was removed under reduced pressure and the residue mixed with H2O and acidified to pH 2 with dilute HCl. The mixture was extracted with EtOAc and the EtOAc washed with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 9.24 g (55% yield) of the product as a solid, mp 191°-193° C. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[C:26]1([C@H:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@@H]2c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)cc1)N1c2ccccc2-c2ccccc2[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from (S)-5-[(4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine* (1.35 g, 3.16 mmol), cyclohexene (6.16 g, 75 mmol), and 1.0 M boron tribromide in dichloromethane (20 mL, 20 mmol) according to the procedure and in the same manner as described in Example 1, step b; and yielded, after chromatographic purification and crystallization from diethyl ether-hexane, 4-{[(S)-6-phenylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.627 g, 1.52 mmol, 48%) as a homogeneous, colorless, crystalline, single enantiomer*, m.p. 210-212° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:12][C:11]([C:14]([F:17])([F:16])[F:15])(O)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(C2CC(O)(C(F)(F)F)ON=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:14]([F:15])([F:16])[F:17])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(C(F)(F)F)CC(c2cccc(F)c2)=NO1
Agent: OC1(C(F)(F)F)CC(c2ccccc2)=NO1
Product: Fc1cccc(-c2cc(C(F)(F)F)on2)c1
Yield: 85.3 %

Procedure:
As described for Example 1b, 3-(3-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-5-ol (60 g, 241 mmol), instead of 3-phenyl-5-hydroxy-5-(trifluoromethyl)isoxazoline, was converted to the title compound (47.5 g, 85%) which was obtained as a light brown solid. MS: m/e=231.1 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:21]=[C:12]3[C:13]4[C:18]([CH2:19][CH2:20][N:11]3[N:10]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:6]=[CH:7][CH:8]=1>O=[Mn]=O.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:21]=[C:12]3[C:13]4[C:18]([CH:19]=[CH:20][N:11]3[N:10]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cc3n(n2)CCc2ccccc2-3)c1
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: COc1cccc(-c2cc3c4ccccc4ccn3n2)c1

Procedure:
To a solution of 2.5 g. of 2-(m-methoxyphenyl)-5,6-dihydro-pyrazolo[5,1-a]isoquinoline in 100 ml. of benzene is gradually added with stirring 30 g. of MnO2 prepared as described by E. Pratt et al., J. Org. Chem. 26, 2973 (1961) and activated according to the procedure of J. M. Goldman, J. Org. Chem. 34, 1979 (1969). The obtained mixture is refluxed with stirring for five days, then filtered. The filtrate after evaporation and crystallization of the solid residue from isopropyl ether gives 1 g. of the title product, m.p. 109°-11° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: C[O-]
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1C=O
Yield: 94.5 %

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (25.0 g, 0.123 mol) and sodium methoxide (13.99 g, 0.2600 mol) in dry methanol (250 mL) was stirred at reflux temperature for 16 hours. The mixture was concentrated and the residue was partitioned between dichloromethane (500 mL) and water (250 mL). The organic layers were combined and dried over sodium sulfate then concentrated in vacuo to provide the title compound as yellow solid (25 g, 94.5%).
Reaction SMILES: [OH-].[Na+].[CH:3]([N:6]1[C:10]2[N:11]=[C:12]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:13]=[C:14]([C:15](OCC)=[O:16])[C:9]=2[CH:8]=[N:7]1)([CH3:5])[CH3:4].[NH2:28][CH2:29][C:30]1[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=1[CH3:36].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO>[CH3:36][C:35]1[CH:34]=[C:33]([CH3:37])[NH:32][C:31](=[O:38])[C:30]=1[CH2:29][NH:28][C:15]([C:14]1[C:9]2[CH:8]=[N:7][N:6]([CH:3]([CH3:4])[CH3:5])[C:10]=2[N:11]=[C:12]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:13]=1)=[O:16]
Reactant: CCOC(=O)c1cc(OC2CCN(C)CC2)nc2c1cnn2C(C)C
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(OC3CCN(C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
Aqueous NaOH (2 equivalent) was added to a solution of ethyl 1-isopropyl-6-((1-methylpiperidin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equivalent) in EtOH (10 times by volume) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using citric acid solution. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was then dissolved in DMSO (10 times by volume) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (2 equivalents) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equivalents) was added to it and stirring was continued for 5 to 16 h. After completion of the reaction, reaction mass was poured into ice water to obtain a solid which was filtered and washed with acetonitrile to provide the desired product (2.5% yield). LCMS: 453.20 (M+1)+; HPLC: 96.37% (@ 254 nm) (Rt; 4.742); 1H NMR (CD3OD, 400 MHz) δ 8.16 (s, 1H), 7.21-7.11 (m, 2H), 7.00 (s, 1H), 6.13 (s, 1H), 5.16-5.11 (m, 1H), 4.53 (d, 2H, J=5.2 Hz), 3.65 (d, 1H, J=13.2 Hz), 3.48-3.45 (m, 2H), 3.38-3.31 (m, 2H), 2.94 (s, 3H), 2.53 (d, 1H, J=12 Hz), 2.41 (s, 3H), 2.40 (m, 1H), 2.25 (s, 3H), 2.20-2.13 (m, 1H), 2.02-1.95 (1H), 1.54 (d, 6H, J=6.8 Hz).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O.CNN>CO>[NH2:3][O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCCC1CON
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a mixture of tert-butyl 2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}piperidine-1-carboxylate 104 (1.50 g, 4.16 mmol) in a solution of methanol (20 mL) was added methylhydrazine hydrate (4.16 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 105 (0.50 g, 53%) as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:5]2=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[C:4]4[N:10]=[CH:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[C:5]4=[N:6][CH:7]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1cnc2c(c1)ncn2CCN1CCCC1
Product: Clc1ccc(-c2ccc(C#Cc3cnc4c(c3)ncn4CCN3CCCC3)nc2)cc1

Procedure:
Prepared according to general working method I from 6-iodo-3-(2-pyrrolidin-1-yl-ethyl)-3H-imidazo[4,5-b]pyridine (300 mg, 0.88 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (187 mg, 0.88 mmol).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:9][C:10]=1[CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:8]2[O:9][C:10]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[C:6]([CH2:4][OH:3])[N:7]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1COC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CO)c(COC3CCCCO3)o2)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
5.3 g 2-(4-Methoxy-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-oxazole-4-carboxylic acid ethyl ester were dissolved in 100 ml tetrahydrofuran and cooled in an ice bath. 21.8 ml of a one molar solution of lithium aluminium hydride in tetrahydrofuran were added. The cooling bath was removed and the reaction mixture stirred at room temperature for thirty minutes. The reaction mixture was cooled in an ice bath again and sequentially added 6 ml water, 12 ml 15% NaOH and 18 ml water. After being stirred for one hour at room temperature the reaction mixture was filtered over a pad of celite and washed with ethyl acetate. The filtrate was dried over MgSO4 and the solvent was removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with n-heptane:ethyl acetate=6:4=>9:1=>ethyl acetate) to obtain 3.0 g [2-(4-methoxy-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-oxazol-4-yl]-methanol.