Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].O[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
0.6 g of N,N'-dicyclodicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 1.0 g of 4-[6-acryloyloxyhexyloxy]benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The combined organic phases are washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which are pure according to thin-layer chromatography gives 0.9 g of 4-(4-[6-acryloyloxyhexyloxy]phenylcarbonyloxy)benzaldehyde.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](O)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[N:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(O)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21

Procedure:
A mixture containing 16 g of 1-ethyl-6-fluoro-7-hydroxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 160 ml of phosphoryl chloride was heated under reflux for 20 minutes with stirring. After evaporation of excess phosphoryl chloride under reduced pressure, the residue was triturated with ice-water and the mixture was stirred for 20 minutes. The resulting precipitate was collected by filtration, washed with water, dried, and recrystallized from acetonitrile to give 14 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 265°-267° C.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[C:13]=1[Cl:14])=[O:8])C.Cl>C(O)C>[Cl:14][C:13]1[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:7]([OH:8])=[O:6]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
A mixture of 12N aqueous solution of sodium hydroxide (0.5 ml), water (2 ml) and ethanol (4 ml) was added to 5-chloro-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (120 mg), and stirred at 80° C. for four hours. After the reaction, 1N hydrochoric acid aqueous solution was added under ice-cooling, the precipitated solid was washed with ethyl acetate to give 5-chloro-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (50 mg).
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[I-:24].[Li+]>CC(C)=O.C(OCC)(=O)C>[C:20]([O:19][C:17]([N:15]1[CH2:16][CH:13]([CH2:12][I:24])[CH2:14]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: [I-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(CI)C1
Temperature: 35 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of 1.94 g of tert-butyl 3-[(tosyloxy)methyl]azetidin-1-carboxylate in 15.5 ml acetone were added 837 mg of lithium iodide and the reaction mixture was stirred for 16 hours at 35° C. After cooling, it was diluted with 200 ml ethyl acetate and the organic phase washed twice with 30 ml portions of water and once with 20 ml saturated sodium chloride solution. After drying over sodium sulphate and filtration, this was concentrated in vacuo. In this manner, 1.6 g of tert-butyl-3-(iodomethyl)azetidin-1-carboxylate were obtained, which was further reacted without purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[CH:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][C:21]1[N:16]2[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[CH:23]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]=3)=[C:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)Nc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CCCC3)n2)ccn1
Agent: [Li]CCCC
Product: CC(C)Nc1cc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)ccn1
Yield: 77.9 %

Procedure:
In a similar manner as described in Example 17 from N-cyclopentyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine (166 mg, 0.401 mmol), n-butyllithium (753 μL, 1.6 M in hexanes, 1.20 mmol) and carbon tetrachloride (155 μL, 1.60 mmol) was formed 4-{7-chloro-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopentyl-2-pyrimidinamine (140 mg, 78%). Rf 0.21 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.36 (d, 1H), 8.19 (d, 1H), 8.07 (d, 1H), 7.36 (m, 1H), 7.13 (d, 1H), 6.90 (d, 1H), 6.81 (s, 1H), 6.52 (d, 1H), 5.25–5.21 (br, 2H), 4.35 (m, 1H), 3.89 (m, 1H), 2.18–2.04 (m, 2H), 1.80–1.50 (m, 6H), 1.22 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CO>C1COCC1>[OH:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(O)cc1C(F)(F)F
Temperature: 80 °C
Yield: 102 %

Procedure:
To a solution of 4-hydroxy-2-(trifluoromethyl)benzoic acid (4.62 g, 22.4 mmol, Fluorochem) in THF (60 ml) at ambient temperature under nitrogen was added dropwise 1.0 M borane-tetrahydrofuran complex (48 ml, 48.0 mmol). The solution was heated to 80° C. for 2 h. To the solution at ambient temperature was added methanol dropwise (40 ml). The solution was heated to 80° C. for 30 min. The solvent was removed in vacuo and the residue dissolved in methanol (100 ml). The solvent was removed in vacuo to leave the title compound as a white solid (4.39 g);
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]3=[CH:11][CH:12]=[CH:13][C:3](=[C:4]23)[CH:2]=1)=O.C1(CC#N)C(C[C:21]#[N:22])=CC=CC=1.C(C=O)=O.[OH-].[Na+].[OH-].[K+]>>[C:21]([C:2]1[C:3]2[C:4](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5]([C:7]#[N:9])=[CH:6][CH:1]=1)#[N:22]
Reactant: N#CCc1ccccc1CC#N
Reactant: O=C1Nc2cccc3cccc1c23
Agent: O=CC=O
Agent: [K+]
Agent: [Na+]
Product: N#Cc1ccc(C#N)c2ccccc12

Procedure:
The naphtholactam compounds of the formula (II) used as starting products are obtainable by reacting o-xylylenedicyanide with glyoxal in the presence of a base (NaOH, KOH) and of a solvent at temperatures below 50° C. (e.g. 0° to 40° C.) to give 1,4-dicyanonaphthalene, and subsequently either
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)=[C:8]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH:9]=1)(=[O:3])[CH3:2]>CCOC(C)=O.C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)=[C:8]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)c[nH]2)c1
Yield: 91 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (g) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [5-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 200 mg, 0.406 mmol). Silica gel chromatography (5-15% EtOAc/DCM) afforded the title compound (134 mg, 91%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.85 (s, 1H), 9.75 (s, 1H), 9.13 (d, 1H, J=1.8 Hz), 8.18 (d, 1H, J=2.5 Hz), 7.75 (dd, 1H, J=8.1, 1.8 Hz), 7.32 (d, 1H, J=8.1 Hz), 5.86 (m, 1H), 2.67 (s, 3H), 2.28-2.35 (m, 2H), 2.08-2.19 (m, 2H), 1.62 (t, 2H, J=6.3 Hz), 1.13 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O2, 363.2 (M+H), found 363.2.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]2[CH2:13][O:12]2)=[CH:4][CH:3]=1.[OH:14][CH2:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[C:8]([C:7]1[C:6]([CH3:10])=[C:5]([CH:11]([OH:12])[CH2:13][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@H:16]2[CH2:15][OH:14])[CH:4]=[CH:3][C:2]=1[F:1])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: Cc1c(C2CO2)ccc(F)c1C#N
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Temperature: 150 °C

Procedure:
A mixture of 6-fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile (785 mg, 4.43 mmol) and (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1340 mg, 6.2 mmol) in ethanol (10 mL) was heated in microwave at 150° C. for 3 h. The volatile was evaporated and the residue was purified on Biotage using 40-100% ethyl acetate/hexane to give the title compound: LC/MS: (M+1)+: 394.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.I[C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:28][CH:29]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:29]=[N:28][C:27]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[CH:26][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Ic1ccc(N2CCOCC2)nc1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(N3CCOCC3)nc2)cc1
Yield: 13.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 4-(5-iodopyridin-2-yl)morpholine (Intermediate-6, 0.139 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 2.0% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.58-3.61 (m, 4H), 3.82-3.85 (br s, 4H), 6.64 (d, J=8.7 Hz, 1H), 7.19 (t, 0.1=8.7 Hz, 1H), 7.36-7.47 (m, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.63-7.67 (m, 1H), 8.03 (d, J=9.0 Hz, 2H), 8.38 (s, 1H), 10.14 (br s, 1H); MS (m/z): 473.64 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[C:23]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=1)#[CH:24].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[Cu]I.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10]([C:24]#[C:23][C:25]3[CH:26]=[C:27]([O:33][CH3:34])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C#Cc2nn(C3CN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
PdCl2(dppf)CH2Cl2 (39 mg) was added to a mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate (200 mg) obtained in Step 2 above, 1-ethynyl-3,5-dimethoxybenzene (117 mg), copper (I) iodide (14 mg), and triethylamine (0.5 ml) in THF (5 ml). After nitrogen purging, the resulting mixture was stirred at 80° C. for 1.5 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (185 mg). Physical properties: m/z [M+H]+ 451.1
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Si:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>C1COCC1.CCCCCC>[C:1]1([C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:36][CH2:35][CH2:34][CH2:33][O:32][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCl
Reactant: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 82.4 %

Procedure:
t-Butylchlorodimethylsilane (8.3 g, 55 mmol) was added to a stirred mixture of 4-chlorobutanol (5.0 mL, 50 mmol), silver nitrate (12.8 g, 75.1 mmol), and pyridine (4.0 mL, 50 mmol) in 40 mL of dry THF. After 4 hr, the reaction mixture was filtered through Celite and evaporated to give a yellow oil. The material was purified by distillation to provide 4-chlorobutyl t-butyldimethylsilyl ether as a colorless oil (11 g, quantitative). To a solution of triphenylmethane (5.10 g, 20.8 mmol) in 25 mL of dry THF at -78° C., 13.1 mL (21 mmol) of 1.6M n-butyllithium was added dropwise under nitrogen. Shortly thereafter, 4.29 g (19.3 mmol) of 4-chlorobutyl t-butyldimethylsilyl ether was added. After addition of water and extraction with hexane, the product was purified by chromatography on silica gel with 1:3 dichloromethane-hexane, providing t-butyldimethylsilyl 5,5,5-triphenylpentyl ether as an oil (6.85 g). This material was dissolved in THF (30 mL) and 16 mL of 1.0M tetrabutylammonium fluoride in THF was added. After 3 hr, the mixture was acidified with 1N HCl, extracted with three portions of ethyl acetate, and the extracts dried over magnesium sulfate and evaporated in vacuo. The product was purified by chromatography on silica gel with a 10%-20% gradient of ethyl acetate in hexane, providing the title compound as a white solid, 3.83 g (63% overall).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=3)=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[K+].Cl>CO.O.[Cl-].[Na+].O>[NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=3)=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Reaction time: 0.67 h
Yield: 84 %

Procedure:
A solution of methyl 6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinate (51 mg, 0.13 mmol) and KOH (37 mg, 0.65 mmol) in 4.0 ml MeOH:H2O (3:1) was heated at 65□C. for 1 hour 40 minutes. The pH of the mixture was adjusted to pH 4 using 10% HCl, brine added, and the aqueous extracted with EtOAc. The combined EtOAc layers were dried with anhydrous Na2SO4 and rotary evaporated. The light yellow solid was triturated with hot EtOAc to give the title compound as an off-white solid (41 mg, 84%).
Reaction SMILES: [ClH:1].Br[CH2:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]([C:11]([CH3:28])([CH3:27])[CH2:12][O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:10])=[CH:6][CH:5]=1.[NH3:31]>>[ClH:1].[ClH:1].[NH2:31][CH2:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]([C:11]([CH3:28])([CH3:27])[CH2:12][O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:10])=[CH:6][CH:5]=1
Reactant: N
Reactant: CN(Cc1ccc(CBr)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Agent: Cl
Product: CN(Cc1ccc(CN)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Yield: 45 %

Procedure:
A solution of 2-[N-(4-bromomethylbenzyl)-N-methylamino]-1-diphenylmethoxy-2-methylpropane hydrochloride (800 mg -- see Example 23) in saturated methanolic ammonia (40 ml) was stirred at room temperature for 18 hours and evaporated. The residue was purified by chromatography on silica (5 g) using methylene chloride plus 0-2% methanol as the eluant. Appropriate fractions were combined and evaporated to give the free base of the title compound (310 mg, 45%) as a colourless oil which was used directly in Example 47. A small portion of the residue was dissolved in ether and the solution was treated with excess saturated ethereal hydrogen chloride. The resulting precipitated oil was collected and triturated with acetone to give the title compound as a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].I([O-])(=O)(=O)=[O:25].[Na+]>[Ru](=O)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:8]2[CH:12]=[N:13][N:14]=[C:7]2[CH3:6])=[C:4]([CH:3]=1)[C:5]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])=[O:25]
Reactant: Cc1nnc2cc(-c3c(F)cccc3F)c3cc(Cl)ccc3n12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 3, 7-chloro-1-methyl-5-(2,6-difluorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-chloro-2',6'-difluoro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[O:8][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1ccc(OCC(=O)c2ccccc2)c(Br)c1

Procedure:
equimolar amounts of 3-bromo-4-hydroxytoluene and α-bromoacetophenone are refluxed in benzene in the presence of potassium carbonate to provide α-(2-bromo-4-methylphenoxy)acetophenone in the usual manner.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.[Cu]=O>[O:7]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: Brc1ccccc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C1CCCc2ccc(Oc3ccccc3)cc21
Temperature: 40 °C
Yield: 78.6 %

Procedure:
A suspension of 60.8 g potassium carbonate in 300 ml of dry pyridine was treated with 35.7 g 7-hydroxy-3,4-dihydro-2H-naphthalen-1-one, and the mixture was heated to 40° C. Thereafter, 19.9 g copper(II) oxide was added thereto with stirring, followed by the drop-wise addition of 39.6 g bromobenzene. The reaction mixture was heated for 4 days under reflux. After evaporating the pyridine completely under vacuum, the residue was stirred with 200 ml ethyl acetate and was filtered through silica gel. The filtrate was washed with saturated solutions of ammonium chloride and sodium chloride, dried over sodium sulfate and concentrated by evaporation under vacuum. The residue was purified by column chromatography, using n-hexane/ethyl acetate as the elutant, whereupon 41.2 g (78.6% of theoretical) 7-phenoxy-3,4-dihydro-2H-naphthalen-1-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[CH2:5][CH:6]1[NH:11][CH2:10][CH2:9][O:8][CH:7]1[CH2:12]2.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCOC(C)=O.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[CH2:28]([O:27][C:25]([N:11]1[CH2:10][CH2:9][O:8][CH:7]2[CH2:12][C:13]3[C:4]([CH2:5][CH:6]12)=[C:3]([O:2][CH3:1])[CH:16]=[CH:15][CH:14]=3)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cccc2c1CC1NCCOC1C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC1C(C2)OCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of 6-methoxy-3,4,4a,5,10,10 a-hexahydro-2H-naphtho-[2,3-b][1,4]oxazine (0.62 g, 2.7 mmol) in 10 ml of CH2Cl2 was added triethylamine (1.0 ml, 7.2 mmol ) and benzyl chloroformate (0.6 ml, 4.1 mmol). The resulting mixture was stirred at 25° C. for 3 h. It was then diluted with 100 ml of EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oily residue which was subjected to column chromatography (20% EtOAc-CH2Cl2) to provide 0.46 g (48%) of the desired product. 1H NMR (300 MHz, CDCl3): δ 2.45 (dd, 1H, J=10.6, 16.6 Hz), 2.83 (dd, 1H, J=10.3, 16.0 Hz), 3.04 (dd, 1H, J=5.0, 16.0 Hz), 3.68-3.88 (m, 6H), 3.76 (s, 3H), 4.02(m, 1H), 5.16 (AB q, 2H, J=17.6 Hz), 6.66 (m, 2H), 7.09 (t, 1H,J=7.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:18])=[CH:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH:11]=[C:10]([Cl:18])[Cl:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C=C(Cl)Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: ClCCl
Product: CC(C)(C=C(Cl)Cl)CCOc1ccc(Cl)cc1
Yield: 86 %

Procedure:
128 g (1 mol) of 4-chlorophenol, 201 g (1 mol) of 1,1,5-trichloro-3,3-dimethyl-1-pentene (II) and 138 g (1 mol) of potassium carbonate in 1 liter of diethylene glycol dimethyl ether are heated under reflux for 10 hours. The mixture is then diluted with methylene chloride and extracted by shaking several times with water. The organic phase is freed of solvent on a rotary evaporator and then distilled at a boiling point of 135°-140° C./0.1 mbar. 252 g (0.86 mol, which is 86% of theory) of 5-(4-chlorophenoxy)-1,1-dichloro-3,3-dimethyl-1-pentene are obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])=[O:15]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccccc1C(F)(F)F

Procedure:
The subtitle compound was prepared from 2-trifluoromethylaniline(10.5 g) and chloroacetyl chloride (6.8 ml) by the method of Example 33 step (iii) as a white solid. Yield: 13.7 g