Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:28]=[CH:27][C:6]2[O:7][CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23]C=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[C:5]=2[CH:4]=1.S(OCCCC1C2C=C(F)C=CC=2OC=1)(C1C=CC(C)=CC=1)(=O)=O.COC1C(N2CCNCC2)=[N:57]C=NC=1>>[ClH:1].[F:2][C:3]1[CH:28]=[CH:27][C:6]2[O:7][CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][N:57]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)[C:5]=2[CH:4]=1
Reactant: COc1cncnc1N1CCNCC1
Reactant: COc1cccnc1N1CCN(CCCc2coc3ccc(F)cc23)CC1
Agent: Cc1ccc(S(=O)(=O)OCCCc2coc3ccc(F)cc23)cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCCc2coc3ccc(F)cc23)CC1

Procedure:
The title compound was prepared (0.31 g, 87%, mp 196°-198° C.) in a manner analogous to the preparation of 1-[3-(5-fluorobenzo[b]furan-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine hydrochloride (Example 20) by the reaction of 5-fluoro-3-benzo[b]furanpropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.[CH3:26][N:27]([CH2:29][CH2:30][CH2:31]Cl)[CH3:28]>>[Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:31][CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)c1
Product: Cc1cccc(-c2nc3ccc(OCCCN(C)C)cc3n2Cc2ccccc2Br)c1

Procedure:
The title compound was prepared essentially as described in Example 116 except that the compound of Example 126 was reacted with 3-(N,N-dimethylamino)propyl chloride. MS 479.
Reaction SMILES: B.[Br:2][C:3]1[CH:10]=[C:7]([C:8]#[N:9])[C:6]([NH2:11])=[CH:5][CH:4]=1.CCO>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:11])=[C:7]([CH:10]=1)[CH2:8][NH2:9]
Reactant: N#Cc1cc(Br)ccc1N
Agent: B
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 125.3 %

Procedure:
A solution of borane in THF (1 M, 400 ml) was added at 0° C. to a suspension of 5-bromo-anthranilonitrile (60 g, 0.304 mol, prepared as described in S. M. Mackenzie et al, J. Chem. Soc. C, 1970, 17, 2298-2308) in THF (450 L), under N2. The mixture was stirred for 72 hours at r.t. After cooling at 0° C. absolute EtOH was added, then HCl was bubbled through the solution. The mixture was concentrated and the residue was suspended in isopropyl ether. The obtained solid was dried to give the di-hydrochloride of the title product (76.6 g, 91.4% yield). C7H9BrN2. 2HCl, MW 273.9; 1H-NMR (200 MHz, d6-DMSO) ppm: 4.13 (s, 2H); 5.82 (s, 4H), 7.24 (d, 1H), 7.55 (dd, 1H), 7.73 (s, 1H), 8.57 (s, 2H). Since the free base is used in the cyclization step, the hydrochloride was suspended in aqueous ammonia, stirred for some minutes after that the free base precipitates. The solid is filtered and dried (yield is quantitative).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1ccc(C(=O)Cc2ccccc2)[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(CCc2ccccc2)[nH]1
Reaction time: 3.5 h

Procedure:
Triethylsilane (0.46 mL, 2.88 mmol) was added to a stirring, room temperature solution of 5-phenylacetyl-1H-pyrrole-2-carboxylic acid ethyl ester (33) (0.240 g, 0.929 mmol) in trifluoroacetic acid (TFA) (2.2 mL, 0.42 M) under N2. The reaction was judged complete by HPLC after 3.5 h. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 60:40 Hexanes:CH2Cl2 to obtain 35, which appeared pure by TLC, but impure by HPLC. Pure 35 was obtained by preparative reverse phase HPLC with the following conditions: 0 to 10 min, 35:65 H2O:CH3CN. 10-11 min, 35:65 to 0:100 H2O:CH3CN; 20 mL/min.; λ=254 nM; 50.8 mg/mL, 0.8 mL/injection. 1H (CDCl3, 400 MHz): δ 9.46 (1H, broad s), 7.33-7.16 (5H, m), 6.85 (1H, t, J=2.9 Hz), 5.99 (1H, t, J=2.9 Hz), 4.29 (2H, q, J=7.1 Hz), 2.97 (4H, s), 1.33 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 161.76, 141.16, 138.18, 128.69, 128.52, 126.46, 121.52, 116.06, 108.46, 60.36, 35.89, 29.83, 14.67 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.67; CH2 carbons: 60.36, 35.89, 29.83; CH carbons: 128.69, 128.52, 126.46, 116.06, 108.46 ppm. HPLC: 10.392 min.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[OH-].[CH2:16]([N+](C)(C)C)[C:17]1[CH:22]=CC=[CH:19][CH:18]=1.ClC(C)(C)C#C>O.ClCCl>[CH3:16][C:17]1([CH3:22])[CH:18]=[CH:19][C:10]2[CH:11]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=[CH:8][C:9]=2[O:12]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Oc1ccc(C2CCCC2)cc1
Agent: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)C=Cc2cc(C3CCCC3)ccc2O1

Procedure:
4-Cyclopentylphenol (10.0 g), and sodium hydroxide pellets (3.7 g) were stirred in water (60 ml) and dichloromethane (60 ml). Benzyltrimethylammonium hydroxide (75 ml, 40% solution in methanol) was added to the solution, followed by 3-chloro-3-methylbutyne (12.63 g) and the reaction mixture stirred under reflux condenser, with sonication. The layers were separated, and the aqueous phase extracted with chloroform. The combined organic layers were evaporated, and the residue taken up in ether. The ether solution was washed with 10% sodium hydroxide solution, and brine and dried over anhydrous magnesium sulphate. Filtration and evaporation gave a pale brown oil (10.89 g) which was refluxed in o-dichlorobenzene (22 ml) under nitrogen for 2 h. Evaporation and chromatography of the resulting brown oil (9.3 g) gave the title benzopyran (4.18 g).
Reaction SMILES: Cl[C:2]([F:26])([F:25])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]([C:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[C:13]=2[OH:24])=[O:11])=[CH:5][CH:4]=1.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[F:26][CH:2]([F:25])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]([C:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[C:13]=2[OH:24])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C1(C)CCC(=O)C(C(=O)c2ccc(C(F)(F)Cl)nc2C)=C1O
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1(C)CCC(=O)C(C(=O)c2ccc(C(F)F)nc2C)=C1O
Yield: 76.8 %

Procedure:
200 mg (0.516 mmol) of methyl 3-[6-(chlorodifluoromethyl)-2-methylpyridine-3-carbonyl]-2-hydroxy-1-methyl-4-oxocyclohex-2-enecarboxylate (compound A94-B34) is heated for 3 hours at a temperature of 120° C. in 8 ml of toluene in the presence of 0.18 ml (0.62 mmol) tris(trimethylsilyl)silane. The viscous residue which remains is chromatographed on silica gel. The pale yellow viscous oil which is obtained by eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 by volume) is dissolved in dichloromethane and washed in succession with aqueous hydrochloric acid and water. Evaporation of the organic solution which has been dried with Na2SO4 yields 140 mg (73%) of pure methyl 3-(6-difluoromethyl-2-methylpyridine-3-carbonyl)-2-hydroxy-1-methyl-4-oxocyclohex-2-enecarboxylate in the form of a pale yellow oil. 1H-NMR (CDCl3): 1.28, s, 3H; 1.79-1.97, m, 1H; 2.39-2.46, m, 1H; 2.43, s, 3H; 2.69, dt (J, 19.2 and 4.8 Hz), 1H; 2.82-2.92, m, 1H; 3.67, s, 3H; 6.55, t, (J, 55.5 Hz), 1H; 7.43, d (J, 7.8 Hz), 1H; 7.49, d (J, 7.8 Hz), 1H; 17.20 ppm, br s, 1H.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6]>C(OC(=O)C)(=O)C.OS(O)(=O)=O>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:5](=[O:6])[CH3:4])[CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:1])[CH3:10]
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Reaction time: 1 h

Procedure:
50 g of 3,5-dihydroxybenzoic acid are suspended in 132.2 g of acetic anhydride and heated to 50°. After the addition of 15 drops of concentrated H2SO4, the resulting solution is stirred for 1 hour at 60°. The reaction mixture is poured onto ice and extracted with CH2Cl2. The combined organic phases are washed 3 times with H2O, dried over Na2SO4 and concentrated by evaporation. The residue is crystallised from ether and yields 3,5-diacetoxybenzoic acid having a melting point of 140°-145°.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[C:21]([C:25]#[C:26][CH2:27][CH2:28]O)[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.Cl.[N-]=[N+]=[N-].[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[N:44]([CH2:28][CH2:27][C:26]#[C:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:45]=[N-:46]
Reactant: CC(C)(C)[Si](Oc1cccc(C#CCCO)c1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc(C#CCCN=[N+]=[N-])c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of alcohol from Step B (375 mg, 0.936 mmol) and diphenylphosphoryl azide (0.242 mL, 1.12 mmol) in toluene (3 mL) at 0° C. was added DBU (0.154 mL, 1.03 mmol). The reaction mixture was stirred at 25° C. for 16 hours, then poured onto 10% HCl (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a brown oil. A solution of the oil and sodium azide (66.9 mg, 1.03 mmol) in DMF (3 mL) was heated to 85° C. for 16 hours. The reaction mixture was poured onto saturated sodium bicarbonate (50 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (0→20% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC(C)(C)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc(O)ccc2C1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
7-Methoxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one (2.25 g, 11.0 mmol) was dissolved in 30 ml CH2Cl2 and cooled to −78° C. Boron tribromide (25.000 ml, 25.0 mmol) was added and the reaction was stirred for 6 h. The temperature was elevated to 0° C. during this time. The mixture was pored into ice and extracted 3×EtOAc (300 ml each). The combined organic extracts were dried over MgSO4 and evaporated. Glass col. Chrom. gave 7-hydroxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one as a yellow solid. MS m/z: 191.1 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](C(O)=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:18]([OH:21])(=[O:20])C.Br>O>[OH:2][C:3]1[CH:4]=[C:5]([C:18]([OH:21])=[O:20])[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: O=C(O)c1cc(O)ccc1-c1ccccc1
Yield: 90 %

Procedure:
25 g of 4'-methoxybiphenyl-4-carboxylic acid, 1 liter of acetic acid and 200 ml of 48% hydrobromic acid were refluxed for 12-14 hours and then the mixture was thrown into 2.5 liter of water. After cooling, the crystals were collected to obtain 4-hydroxybiphenylcarboxylic acid with a melting point of 288°-291° C. and at a yield of 90-95%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]([CH3:39])[C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH:35]([CH3:39])[C:36]([NH2:38])=[O:37])=[CH:7][CH:6]=3)[C:9]([CH3:33])=[N:10][C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C(N)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.5 %

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.00 g) and 2-bromopropanamide (0.70 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.50 g), and the mixture was stirred at 80° C. for 15 hr. After allowing to cool, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.03 g, 88%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(=O)([O-])[O-]>CN(C=O)C.C(OCC)(=O)C>[P:20]([O:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: CCOP(=O)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1.5 g) and diethyl chlorophosphate (2 ml) in DMF (20 ml) there was added a powdered mixture of potassium carbonate (2 g) and potassium iodide (2 g). The reaction mixture was stirred at room temperature. After 30 minutes, a further addition of potassium carbonate and potassium iodide (2 g each) was made and stirring was continued. Two hours later more carbonate (2 g) and diethyl chlorophosphate (2 ml) were added, and then three hours later a final addition of carbonate (2 g) was made. The mixture was stirred for 3 days then diluted with ethyl acetate (60 ml) and the insolubles filtered. The filtrate was washed with water, dried and evaporated down. This residue was crystallized from acetone, then chromatographed on a column of silica gel, eluting first with 1:1, then 3:1 mixtures of ethyl acetate and hexane to afford pure title compound (337 mg), m.p. 162°-163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[SH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]2)=[CH:16][CH:15]=1>>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:5]=[CH:4][C:3]2[S:12][C:25]([CH2:26][CH:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[CH2:21][C:22]([OH:24])=[O:23])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Product: O=C(O)CC(Cc1nc2cc(C(F)(F)F)ccc2s1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.55, starting from 2-amino-4-trifluoromethylthiophenol and 3-(4-chlorophenyl)glutaric anhydride, 4-(5-trifluoromethyl-2-benzothiazolyl)-3-(4-chlorophenyl)butanoic acid was obtained as colourless solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:24]=[C:23]([CH3:25])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19](=O)[NH:20][CH:21]=3)=[C:10]([CH3:26])[CH:9]=2)[N:4]=1.CI.[C:31]([O-:34])([O-])=O.[K+].[K+]>COCCOCCN(CCOCCOC)CCOCCOC.CN(C=O)C>[F:27][C:2]([F:1])([F:28])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[C:31](=[O:34])[N:20]([CH3:21])[CH:19]=[CH:18][CH:17]=3)=[C:23]([CH3:25])[CH:24]=2)[N:4]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1cccn(C)c1=O
Yield: 91.7 %

Procedure:
To a solution of 0.95 g (2.41 mmol) of 5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-2 (1H)-pyridone, 20 drops of TDA-1, and 0.5 ml of methyl iodide in 50 ml of dry DMF was added 0.96 g (3 eq) of milled K2CO3. The mixture was filtered and concentrated in vacuo to afford 0.9 g (91.8%) of 3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-1-methyl-2-pyridone, as a white solid, which was recrystallized from isopropyl acetate to yield a white solid, 143°-146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[N:16]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[N:16]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:32])=[O:31]
Reactant: Nc1cccc(CC(=O)Nc2nc(-c3c[nH]c4ncccc34)cs2)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(NS(=O)(=O)CCCCl)c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Amino-phenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (100 mg, 0.28 mmol) was dissolved in DMF (5 mL) and 3-chloro-propane-1-sulfonyl chloride (1 eq, 35 □L) was added followed by triethylamine (2 eq, 80 □L). The reaction mixture was stirred at RT for 3 hours and then diluted with EtOAc and extracted with water. The organic layer was dried and concentrated to give brown oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33])#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:30]=[CH:31][C:32]([F:33])=[C:27]([CH:28]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(F)c(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 31.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-cyano-4-fluorophenylboronic acid (17 mg, 0.104 mmol). The mixture was heated under Ar at 120° C. under microwave for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative HPLC twice to give pure 5-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-2-fluorobenzonitrile (7 mg, 32%). 1H-NMR (MeOD): 2.15 (m, 1H), 2.29 (t, 1H), 3.12 & 3.18 (s, 3H), 5.30 & 5.89 (m, 1H), 7.03 (m, 1H), 7.21 (m, 1H), 7.31-7.50 (m, 6H), 7.85 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH2:13](Br)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>CO>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CSc1nc2ccccc2[nH]1)c1ccccc1
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a suspension of 2-Mercaptobenzimidazole (0.06M, 9 g) in methanol (50 ml) was added sodium hydroxide (0.06M, 2.4 g) and stirred for 30 min. to get a clear solution. To this solution, phenacyl bromide (0.05M, 10 g) was added slowly and stirred until the solid separates. The solid was filtered and washed thoroughly with 5% sodium hydroxide solution and methanol to get white solid (11.2 g). M.P. 167° C. NMR (DMSO): δ5.1(s, 2H, CH2), 7-8.2(m, 10H, Aromatic).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1
Reactant: COc1ccc(C=O)cc1Cl
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1Cl

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-chloro-4-methoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 3-(3-Chloro-4-methoxy-benzylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 205-208° C.; HPLC: TRet (Grad20-100)=12.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[N:5]=[C:4]2[CH:12]=[CH:13][S:14][C:3]=12.[Li+].[OH-]>>[OH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]2[CH:12]=[CH:13][S:14][C:3]=12
Reactant: COC(=O)c1cc(O)c2sccc2n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc(O)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A sample of methyl 7-hydroxythieno[3,2-b]pyridine-5-carboxylate is hydrolyzed by the addition of 2.5 equivalents of aqueous lM LiOH and stirred for 16 hours at RT. The aqueous reaction mixture is extracted 2x with ethyl acetate and acidified to pH 2.0 with aqueous lN HCl. The resulting precipitate is filtered, washed with water and dried to afford 7-hydroxythieno[3,2,b]pyridine-5-carboxylic acid.