Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1>C(Cl)Cl.[Cl-].[Na+].O>[Br:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([Cl:3])=[N:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cncc(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
As shown in step 2-iv of Scheme 2, phosphorous oxychloride (48.02 g, 403.6 mmol) was added to 3-bromo-5-ethoxypyridine, 1-oxide (4.4 g, 20.18 mmol) in 700 mL of DCM at RT. The reaction mixture was stirred at RT overnight. After the addition of brine, the organics were partitioned, dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The product was purified by filtering the concentrate through a pad of silica gel and eluting the pad with ethyl acetate. The volatiles were removed under reduced pressure to provide 5-bromo-2-chloro-3-ethoxypyridine (Compound 1003, 4.3 g, 85.6%): 1H NMR (CDCl3) δ 8.1 (s, 1H), 7.32 (s, 1H), 4.15 (q, 2H), 1.6 (t, 3H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:50])[CH3:49])=[CH:44][C:43]=1[N+:51]([O-:53])=[O:52])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:50])[CH2:49][Br:1])=[CH:44][C:43]=1[N+:51]([O-:53])=[O:52])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
Phenyltrimethylammonium tribromide (1.46 g, 3.90 mmol) was added to a solution of 1-(4-benzyloxy-3-nitrophenyl)ethanone (2) (1.04 g, 3.82 mmol) in anhydrous THF (15 mL) in three portions. The reaction mixture was stirred at rt for 12 h. Then an aqueous sodium bicarbonate solution (5%, 10 mL) and an aqueous sodium thiosulfate solution (10%, 5 mL) were added. The mixture was extracted with dichloromethane, and combined organics were concentrated by rotary evaporation. The resulting residue was purified by Biotage silica gel column chromatography eluting with dichloromethane to give bromo ketone 3 as a white solid (1.08 g, 81% yield): 1H NMR (500 MHz, CDCl3) δ 4.49 (s, 3H), 5.35 (s, 2H), 7.21 (d, 1H), 7.40 (m, 5H), 8.15 (dd, 1H), 8.49 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 2 h

Procedure:
To a solution of methyl 3-benzyloxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (50 mg, 0.17 mmol) in anhydrous DMF at 0° C. was added NaH (6 mg, 0.25 mmol, 95% dispersion in oil). Once gas evolution had ceased, the mixture was treated with 4-fluorobenzyl bromide (31 μL, 0.25 mmol) and was stirred for 2 hours. The reaction was quenched by the addition of a few drops of water. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. ES MS (M+1)=410.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:41])[C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:41])[C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(tert-butoxycarbonylamino)-N-[7-(tert-butyldiphenylsilyloxy)naphthalen-1-yl]propionamide (290 mg, 0.51 mmol) in dry THF (2 mL), under argon, was added TBAF (0.56 mL of a 1.0 M solution in THF, 0.56 mmol) dropwise. The resulting mixture was stirred at ambient temperature for 30 min, then saturated aqueous NaHCO3 (1 mL) was added and the THF was removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted further with CH2Cl2 (30 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2-10% to 30% EtOAc to yield the titled product as a pale solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][S:4][C:3]=1[C:14]([O-:16])=O.[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[NH2:34])=[CH:21][CH:20]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[NH:34][C:14]([C:3]2[S:4][CH:5]=[C:6]([CH2:7][N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[C:2]=2[Cl:1])=[O:16])=[CH:23][CH:24]=1
Reactant: O=C([O-])c1scc(CN2CCOCC2)c1Cl
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CN2CCOCC2)c1Cl
Reaction time: 0.75 h
Yield: 16 %

Procedure:
To a mixture of sodium 3-chloro4-(morpholin-4-yl)methyl-2-thiophene carboxylate (1.0 g, 3.9 mmol) and N-(4-chlorophenyl)-2-amino-5-chlorobenzamide (0.88 g, 3.1 mmol) in pyridine (20 mL) at −10° C. was added POCl3 (0.40 mL, 4.3 mmol). After 45 minutes, the mixture was poured onto ice-water and the resulting solid collected by filtration. Crystallization from 1-butanol afforded 0.26 g (13% yield) of N-(4-chlorophenyl)-2-[((4-(morpholin-4-yl)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a tan solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (d, 2), 7.4 (d, 3), 3.6 (s, 2), 3.3 (br, 4), 2.4 (br, 4) ppm.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([NH2:11])=[O:10])=[N:5][CH:4]=1)#[CH:2].[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](I)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]([C:2]#[C:1][C:3]4[N:7]([CH3:8])[C:6]([C:9]([NH2:11])=[O:10])=[N:5][CH:4]=4)[CH:34]=3)=[O:37])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: C#Cc1cnc(C(N)=O)n1C
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc(C(N)=O)n1C

Procedure:
This was made as for example 2 using 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide and N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide: MS (M+H)+ 493.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][C@@H:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: O=S(=O)(OC[C@@H]1CCCCO1)C(F)(F)F
Product: COc1cn(C(C[C@@H]2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
237 mg (0.55 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 0.72 ml (0.72 mmol, 1.3 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were reacted with 274 mg (1.11 mmol, 2.0 eq.) of (2S)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate according to General Method 7B. Yield: 130 mg (45% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([NH2:25])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Na+].P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]#[N:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxamide (12 mg, 0.034 mmol) was suspended in dichloroethane (0.2 ml). Sodium chloride (70 mg) was added followed by Phosphorus oxychloride (20 ul). The mixture was stirred at 80° C. for 1.5 hours. An extra amount of Phosphorus oxychloride (50 ul) was added and the mixture was heated at 80° C. for 8 hours. The volatiles were removed in vacuo. Water was added and the solid was filtered. The material was purified by preparative TLC on silica gel (5% MeOH in CH2Cl2) to provide 6 mg of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carbonitrile. LCMS (ES): >95% pure, m/z 331 [M+1]+.
Reaction SMILES: [C-:1]1([CH2:6][C:7](Cl)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].N1C=CC=CC=1.[OH2:22]>CN(C)C1C=CN=CC=1>[C-:1]1([CH2:6][C:7]([OH:8])=[O:22])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: O=C(Cl)C[c-]1cccc1
Reactant: O
Agent: [Fe+2]
Agent: CN(C)c1ccncc1
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Product: O=C(O)C[c-]1cccc1
Reaction time: 0.17 h

Procedure:
A 50 ml round-bottom flask, equipped with magnetic stirrer and nitrogen inlet, is charged with 0.50 g (0.19 mmol) of ferrocene acetic acid chloride (prepared in analogy to a process slightly modified from Macromolecules 26 (1993) 1936-1940), 10 ml of pyridine, 1.28 g (0.95 mmol) of brominated and, hydroxymethylated tetra(α-2,4-dimethyl-3-pentyloxy)-palladium-phthalocyanine and 12 mg (0.1 mmol) of 4-dimethylaminopyridine under argon, and the dark green solution is stirred for 20 hours at room temperature. The reaction mixture is then poured, with thorough stirring, on 100 ml of water and the precipitate is collected by filtration and washed with 4×50 ml of water. After drying the residue for 4 hours at 60° C. and 125 torr, it is dissolved in 15 ml of toluene and then 1.3 g of silica gel are added and the mixture is stirred for 10 minutes. The suspension is filtered and the residue is washed with 3×10 ml of toluene. Using a rotary evaporator, the filtrate is concentrated by evaporation to 4.8 g of a solution which is then poured, with stirring, on 49 ml of acetonitrile and stirred for 10 minutes. The precipitate is collected by filtration, washed with 3×50 ml of acetonitrile and dried overnight at 60° C. and 125 torr, yielding 1.2 g (80.5% of theory) of a green powder (brominated and hydroxymethylated tetra(α-2,4-dimethyl-3-pentyloxy)palladium-phthalocyanine which is esterified with ferrocene acetic acid) having the following analytical values: Elemental analysis: 12.71% Br, 4.49% Fe UV/VIS (NMP): λmax=723 nm, ε=148170 l·mol−1·cm−1 IR: C═O band for ester (cm−1) present TGA: point of inflection of the decomposition curve=278° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C1C(=O)N([Br:17])C(=O)C1.OS([O-])=O.[Na+]>C(#N)C>[Br:17][C:8]1[C:7]([F:9])=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(F)cc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1cc(F)c(Br)c(Cl)c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 95.3 %

Procedure:
3-Chloro-5-fluoroaniline (2061 mmol, 300 g) was dissolved in ACN (3000 ml) and the solution cooled to 0° C. NBS (2061 mmol, 367 g) was added to the reaction mixture in small portions keeping the temperature below 10° C. Reaction mixture was stirred at 10±5° C. for 3.5 h. 10% Aqueous NaHSO3 was added and the reaction mixture was concentrated under vacuum to remove organic solvents. Water and DCM was added, stirred for 15 min and the phases were separated. The water phase was extracted with DCM. The combined organics were washed with water. The organic phase was evaporated. 2-Propanol was added to the residue and distilled until the steam temperature was 80° C. Water was added and the temperature was kept at 40±10° C. The mixture was cooled to 5° C. and stirred for 4 h. The precipitate was removed by filtration, washed with water and dried under vacuum. 440.7 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 5.87 (s, 2H), 6.42-6.49 (m, 1H), 6.62-6.66 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.C([O-])(=[O:15])C.[K+].Cl>[OH-].[Na+].O1CCOCC1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][OH:15])[C:7]=2[CH:8]=1
Reactant: CC(=O)[O-]
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: OCc1csc2ccc(Cl)cc12

Procedure:
A solution of 3-bromomethyl-5-chlorobenzothiophene (2.5 g, 9.56 mmol) and potassium acetate (1.96 g, 20 mmol) in 1M NaOH (40 mL) and dioxane (40 mL) was heated to reflux for 24 hours, adjusted to pH<7 with 1M HCl, and extracted with ethyl acetate (3×). The combined extracts were washed with brine, concentrated, and purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[CH:8]=1.CN(C)[CH:17]=[O:18]>>[CH2:13]([C:9]1[CH:8]=[C:7]([CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=1)[CH3:14]
Reactant: CCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CCc1cccc(CO)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (34 ml of a 2.5M solution in hexanes) was added to a solution of 1-bromo-3-ethylbenzene (15 g) in tetrahydrofuiran (320 ml) at -78° C. After 1 hour dimethylformamide (15 ml) was added. The mixture was stirred at -78° C. for 1 hour and allowed to warm to room temperature. The mixture was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in methanol (250 ml) and treated with sodium borohydride (1.51 g) portionwise. The mixture was stirred at room temperature for 16 hours, quenched with 2M HCl (100 ml) and stirred for 4 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 2M HCl. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography eluting with 5-10% ethyl acetate in isohexane. Yield 7.6 g.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[CH2:37][CH2:38]O>C1COCC1>[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[CH2:37][CH2:38][O:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: N#Cc1cccc(-n2nc(C(F)(F)F)cc2O)c1
Reactant: COc1ccccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COc1ccccc1CCOc1cc(C(F)(F)F)nn1-c1cccc(C#N)c1
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
A suspension of 130 (200 mg, 0.790 mmol) and PS-PPh2 (2.15 mmol/g, 0.522 g, 1.5 eq, polymer supported triphenylphosphine) in THF (7 mL) under a nitrogen atmosphere was stirred for 10 minutes. DIAD (0.154 mL, 0.790 mmol) was added and after 1 hour of stirring at room temperature 2-methoxy-phenethyl alcohol (0.112 mL, 0.790 mmol) was added and the suspension was stirred for 48 h. The reaction mixture was filtered and the resin washed with DCM, the filtrate was concentrated and the residue purified by silica gel chromatography (Biotage 25M, 5-20% ethyl acetate in hexanes) to give 131 (86 mg, 0.222 mmol, 28.1% yield) as white solid. LRMS(ESI): (calc.) 387.4 (found) 388.1 (MH)+, 410.0 (MNa)+.
Reaction SMILES: C([C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:16][CH:15]=2)[C:9]=1[OH:10])(O)=O.NC1C=CC=CC=1>>[OH:10][C:9]1[N:8]2[N:11]=[CH:12][C:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[CH:18][CH:19]=3)=[C:7]2[N:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(Cc2ccc(-c3cnn4c(O)c(C(=O)O)cnc34)cc2)c1
Solvent: Nc1ccccc1
Product: Cc1cccc(Cc2ccc(-c3cnn4c(O)ccnc34)cc2)c1
Temperature: 0 °C
Yield: 39.6 %

Procedure:
A mixture of 6-carboxy-7-hydroxy-3-[4-(3-methylphenylmethyl) phenyl]pyrazolo[1,5-a]pyrimidine (1.44 g) and aniline (10 ml) was heated at 100° C. to 110° C. with stirring, and reacted with each other for 1 hour. After completion of reaction, ice-water (100 ml) was poured into the mixture, and the precipitate was filtrated, washed with water and 30% methol, dried, and separated and purified by using a silica-gel column chromatography (chloroform:methanol=30:1) to give the title compound (0.50 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Br:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[Br:21][C:22]1[N:23]=[CH:24][N:25]([C:2]2[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:26]=1
Reactant: Brc1c[nH]cn1
Reactant: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-isopropyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.43) (0.4 g, 1.33 mmol) and commercially available 4-bromo-imidazole (0.29 g, 2.0 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.5 g, 91%). MS (ISP) 413.1 [(M+H)+]; mp 185° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=3[F:34])[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1c(F)cccc1F
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2c(F)cccc2F)nn1
Yield: 28.2 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (48 mg, 0.14 mmol); 2-azido-1,3-difluorobenzene (24 mg, 0.15 mmol); CuSO4 (3.5 mg, 0.02 mmol); NaAsc (18 mg, 0.09 mmol); TBTA (12 mg, 0.01 mmol); in t-BuOH/EtOH/H2O (1:1:0.5); afforded 46 as a white solid (20 mg, 31.6%). 1H NMR (DMSO-d6, 400 MHz): δ 8.74-8.73 (d, 1H, J=1.79 Hz); 7.74-7.72 (m, 2H); 7.55-7.45 (m, 1H); 7.34-7.32 (m, 1H); 7.17-7.13 (t, 2H); 7.04-7.03 (d, 1H, J=1.72 Hz); 4.82-4.80 (q, 1H); 4.57-4.56 (d, 2H, J=5.97 Hz); 4.29-4.24 (m, 2H); 3.71-3.70 (d, 1H, J=1.78 Hz); 3.55-3.54 (d, 1H, J=1.78 Hz); 3.35-3.18 (m, 2H); 1.33-1.30 (t, 3H). 13C NMR (CDCl3, 100 MHz): 170.16, 166.65, 166.30, 158.01, 155.46, 153.29, 152.24, 144.36, 131.48, 129.14, 125.10, 116.01, 112.64, 62.24, 53.81, 52.74, 52.62, 34.74, 32.91, 13.99.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2)=O)(C)(C)C.[ClH:24].CO>>[ClH:24].[CH:18]1[C:19]2[C:14](=[C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH:8][CH3:6])[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][N:17]=1
Reactant: CN(CCCNc1cccc2cnccc12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCCCNc1cccc2cnccc12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 31 hours) by using Intermediate 29 (325 mg) and 10% hydrogen chloride/methanol solution (5 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (273 mg) as light yellow powdery solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:19])([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:18])([CH3:19])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC1=Cc2cc(Sc3cccc(O)c3)ccc2OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1=Cc2cc(Sc3cccc(O[Si](C)(C)C(C)(C)C)c3)ccc2OC1(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
6-(3-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.2 g) (see Preparation 9) was dissolved in dry dimethylformamide (4 ml) and imidazole (1.1 g) and tert-butyidimethylsilyl chloride (1.2 g) were added. The flask was fitted with a calcium chloride drying tube and the mixture was stirred at 40° C. for one hour. Water was added and the mixture was extracted with diethyl ether. The organic extract was washed with aqueous sodium hydrogen carbonate solution (×2), dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product chromatographed on silica using (4:1 hexane: dichloromethane as the eluent to yield 6-(3-tert-butyldimethylsilyloxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.84 g) as an oil.