Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[C@:13]3([CH2:22][C@:21]3([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:23]([CH3:25])[CH3:24])[C:12]2=[O:34])[CH:5]=1.[OH-].[Na+].Cl>O1CCCC1.O.C(OCC)(=O)C>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C@@:21]2([CH:23]([CH3:25])[CH3:24])[C@@:13]3([C:14]4[C:19](=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)[N:11]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:35])=[O:2])[C:12]3=[O:34])[CH2:22]2)=[CH:31][CH:30]=1)#[N:33]
Reactant: COC(=O)c1cccc(CN2C(=O)[C@@]3(C[C@]3(c3ccc(C#N)cc3)C(C)C)c3cc(F)ccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[C@@]1(c2ccc(C#N)cc2)C[C@@]12C(=O)N(Cc1cccc(C(=O)O)c1)c1ccc(F)cc12
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of (1S,2S) and (1R,2R)-methyl-3-((2-(4-cyanophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoate (500 mg, 1.1 mmol) in tetrahydrofuran (10 mL) was added 30% sodium hydroxide in water (3 mL) at room temperature and the mixture was stirred at that temperature for 16 hours. The mixture was neutralized with 2 N aqueous hydrochloric acid solution, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoro-acetic acid in water) afforded the title compound (270 mg, 59.5%) as a white solid: LC/MS m/e calcd. for C28H23FN2O3: 454, observed (M+H)+: 455.2 1H NMR (400 MHz, MeOD-d4) δppm 7.97 (s, 1 H), 7.94 (d, J=7.83 Hz, 1 H), 7.85 (dd, J=7.96, 1.64 Hz, 1 H), 7.67 (dd, J=7.96, 1.39 Hz, 1 H), 7.61 (d, J=7.58 Hz, 1 H), 7.48 (q, I=7.83 Hz, 2 H), 6.74-6.86 (m, 3 H), 5.28 (d, I=15.92 Hz, 1 H), 5.17 (dd, J=8.72, 2.40 Hz, 1 H), 4.97 (d, J=16.17 Hz, 1 H), 3.04 (dt, J=13.64, 6.82 Hz, 1 H), 2.23-2.28 (m, 1 H), 2.20-2.23 (m, 1 H), 0.92 (d, J=7.07 Hz, 3 H), 0.81 (d, J=6.82 Hz, 3 H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17](=[S:19])[N:16]([CH3:20])[C:15]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)=[CH:10][CH:9]=1.Cl[CH2:32][C:33]([N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38])=[O:34]>CC(C)=O>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([C:15]2[N:16]([CH3:20])[C:17]([S:19][CH2:32][C:33]([N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38])=[O:34])=[N:18][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH:26]=[CH:25][N:24]=1)(=[O:30])[CH3:29]
Reactant: O=C(CCl)N(CCO)CCO
Reactant: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)[nH]c(=S)n2C)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nc(SCC(=O)N(CCO)CCO)n2C)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
K2CO3 (3.1 mmol/0.34 g) is added to undissolved N-{4-[5-(4-fluorophenyl)-3-methyl-2-thioxo-2H-imidazol-4-yl]pyridin-2-yl}acetamide (2.23 mmol/0.8 g), and the mixture is then suspended in 100 ml of absolute acetone. 2-Chloro-N,N-bis(2-hydroxyethyl)acetamide (2.3 mmol/0.455 g) is then added, and the mixture is stirred at room temperature for 24 h. The mixture is then heated under reflux for 3 h, the precipitate is filtered off and the filtrate is concentrated under reduced pressure using a rotary evaporator. The oily residue is separated on a column (mobile phase: CH2Cl2/EtOH, 9.5:0.5).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(I)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)c(-c2ccccc2)c1
Yield: 55.7 %

Procedure:
In a schlenck tube, a mixture of 2-chloro-3-iodo-5-nitropyridine (1.76 mmol, 0.5 g), phenylboronic acid (1.94 mmol, 0.24 g), PdCl2dppf.DCM (0.18 mmol, 0.1 g), Cs2CO3 (5.28 mmol, 1.7 g) in a dioxane/water 4:1 mixture (6.5 ml) was heated at 120° C. for 4 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/dichloromethane mixtures affording 2-chloro-5-nitro-3-phenylpyridine (0.23 g, yield 55%) of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>C1CCCCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:26])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: C1CCCCC1
Product: CCOC(=O)CC(=Nc1ccc(C(=O)OCC)cc1)c1ccccc1

Procedure:
4-Amino-benzoic acid ethyl ester (66 g, 0.4 mol) and 3-oxo-3-phenyl-propionic acid ethyl ester (0.4 mol, 1 eq.) were dissolved in 500 mL cyclohexane and refluxed for 2 days using a Dean-Stark trap. The solution was filtered, the solvent evaporated and the residue recrystallized to give 4-(2-ethoxycarbonyl-1-phenyl-ethylideneamino)-benzoic acid ethyl ester (Compound 481a) MS: 340.18 (M+H+). 4-(2-Ethoxycarbonyl-1-phenyl-ethylideneamino)-benzoic acid ethyl ester was dissolved in diphenyl-methanone (250 mL) and heated to 250° C. for 4 hr. The resulting solution was diluted with diethyl ether and filtered to give 48.6 g of the title intermediate as a white crystalline solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[Br:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]>CCCCCC>[Br:9][C:10]1[CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1Br)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Br)c2)n1
Reaction time: 0.67 h
Yield: 46.5 %

Procedure:
Sodium hydride (60% suspension in oil, 1.2 g, 30.15 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (110 mL). Neat 3-methylpyrazole (2.47 g, 30.15 mmol) was added dropwise at 0° C. After the gas evolution subsided the cooling bath was removed and stirring was continued at room temperature. The [2-bromo-4-fluorophenyl]- (5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step B (6 g, 18.07 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 40 minutes, cooled and partitioned between water and ethyl acetate. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 75:25) provided the less polar title compound (3.87 g) along with a mixture of 3- and 5-methylpyrazole regioisomers (0.860 g). The title compound (3.5 g, 51%) crystallized by sonication from hexane-ethanol, m.p. 208-209° C. (dec).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)=O)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32]>>[CH2:29]([NH:33][C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:8][CH2:9][CH2:10][CH2:11][CH3:16])[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:7][CH2:6][CH2:5][CH2:4][CH3:3])[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CS(=O)c1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(S(C)=O)n2)n1
Reactant: CCCCN
Product: CCCCNc1nccc(-c2nn3c(NCCCC)cccc3c2-c2ccnc(NCCCC)n2)n1

Procedure:
N-Butyl-2,3-bis[2-(butylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine was prepared by treating 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine with n-butylamine as described in Example 7. 1H NMR, (400 MHz, CDCl3): δ 8.35 (d, 1H), 8.09 (d, 1H), 7.62 (d, 1H), 7.30 (t, 1H), 6.93 (m, 1H), 6.57 (d, 1H), 6.40 (d, 1H), 6.20 (d, 1H), 5.17 (m, 1H), 5.08 (m, 1H), 3.34–3.46 (m, 6H), 1.75 (m, 2H), 1.35–1.66 (m, 10H), 0.90–1.00 (m, 9H); MS m/z 488 (M+1).
Reaction SMILES: CC1C=CC([C@@H](N[C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])C)=NC=1.Cl.[CH2:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C@@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1)[CH3:24]>>[CH2:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C@@H:32]([NH:34][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH3:33])=[CH:28][CH:27]=1)[CH3:24]
Reactant: CCOc1ccc([C@H](C)N)cn1
Reactant: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1
Agent: Cl
Product: CCOc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 2 using IM46 and commercially available (S)-1-(6-ethoxy-pyridin-3-yl)-ethylamine hydrochloride (Supplier Sial Gmbh, Catalog No 528261-HCl, Lot no LNA098). Yield=0.30 g (39%). 1H NMR (500 MHz, DMSO) δ 8.54 (d, 1H), 8.08 (s, 1H), 7.82 (d, 1H), 7.27 (m, 2H), 7.16 (m, 1H), 7.12 (d, 2H), 8.73 (d, 1H), 4.92 (m, 1H), 4.25 (q, 2H), 2.20 (m, 1H), 1.91 (m, 1H), 1.35 (m, 4H), 1.30 (t, 3H), 1.19 (m, 1H). LC-MS (m/z) 311.4 (MH+), tR=1.45 min (method A).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(O)C>[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:2][OH:3])[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: NO
Reactant: CCCC(=O)c1ccc(OCOC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCC(=NO)c1ccc(OCOC)cc1
Yield: 77.3 %

Procedure:
Hydroxylamine hydrochloride (2.7 g, 39.4 mmol) was added to a stirred solution of 1-(4-(methoxymethoxy)-phenyl)butan-1-one (4.1 g, 19.7 mmol) and pyridine (94.67 g, 59.1 mmol) in ethanol (30 mL), and the mixture heated to reflux for 1.5 hours then allowed to cool. Most of the ethanol was removed by concentration under reduced pressure, and the residue was partitioned between water and dichloromethane. The layers were separated and the aq phase extracted 2× with dichloromethane. The combined extracts were washed twice with water, then with saturated brine and dried over magnesium sulfate. The solvent was removed in vacuo, leaving 5.1 g of slightly cloudy, colorless syrup, which was flash chromatographed on a column (50×70 mm) of silica gel eluting with Hxa/EtOAc/acetone 8:1:1 to afford 3.4 g (77%) of snow-white crystalline solid; mp 74-76° C.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH2:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3O)=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.P(Cl)(Cl)([Cl:29])=O>C(#N)C>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH2:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:29])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(-n2cccn2)cc1
Solvent: CC#N
Product: CCc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture containing 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2-ethylquinolin-4-ol (1.78 g, 4.36 mmol, Intermediate 32: step c) and phosphorus oxychloride (1.8 mL, 20 mmol) in acetonitrile (15 mL) was heated to 90° C. After 3 hours, the flask was allowed to cool to 23° C. The mixture was concentrated. Dichloromethane (100 mL) and ice (50 mL) were added to the residue. Concentrated aqueous ammonia solution was added dropwise with stirring until the pH was 9 by litmus paper test. The biphasic mixture was stirred at 23° C. for 30 minutes. The layers were separated. The aqueous layer was extracted with dichloromethane (25 mL). The organic layers were combined and the combined solution was dried with sodium sulfate. The dried solution was filtered. Celite® (8 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with hexanes initially, grading to 25% ethyl acetate-hexanes provided the title compound as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C3CCCCO3)[CH:26]=2)[S:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])(=[O:14])=[O:13])=[CH:7][CH:6]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCCC1.C(OCC)(=O)C>[OH:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:10][CH:9]=1)[S:12]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])(=[O:14])=[O:13]
Reactant: C1CCNCC1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCCBr)cc2)c(C)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(OCCN3CCCCC3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
To a solution of N-[4-(2-bromo-ethoxy)-phenyl]-2,4,6-trimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (0.070 g, 0.12 mmol) in 2 mL tetrahydrofuran was added piperidine (0.12 mL, 1.21 mmol). The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted to a volume of 30 mL with ethyl acetate and was washed with saturated aqueous sodium bicarbonate (2×15 mL) and saturated aqueous sodium chloride (1×15 mL). The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (5% methanol/methylene chloride) afforded 0.010 g of an oil. The oil was further purified by preparative TLC (0.5 mm silica gel layer, eluting with 10% methanol/methylene chloride) to afford 0.003 g of the title compound. MS 509.2 (M+1)+
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])C>O.C1COCC1.CO>[OH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][CH2:7][C:6]([OH:18])=[O:5])=[O:17]
Reactant: CCOC(=O)CNC(=O)c1ccccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccccc1O
Yield: 93 %

Procedure:
LiOH in water (82 mg in 2 mL of water) was added dropwise to (2-hydroxy-benzoyl amino)-acetic acid ethyl ester (110 mg, 0.49 mmol) in a mixture of THF and MeOH. The THF and MeOH were evaporated under reduced pressure and the residue was acidified using 10% citric acid solution. The product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford (2-hydroxybenzoyl amino)-acetic acid in 93% yield. 1H NMR (DMSO-D6): δ 12.8 (s, 1H), 12.2 (s, 1H), 9.2 (t, 1H), 7.9 (d, 1H), 7.5 (dt, 1H), 7.0 (d, 2H), 4.0 (d, 2H).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH2:13]O)=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.S(Cl)(C)(=O)=O.C(N(CC)CC)C.CCN(C(C)C)C(C)C.[C:36]1([C:42]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl.CN(C1C=CN=CC=1)C>[F:10][C:9]([F:12])([F:11])[C:6]1[N:5]=[C:4]2[CH2:13][N:43]([C:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:2][C:3]2=[CH:8][CH:7]=1
Reactant: OCc1ccc(C(F)(F)F)nc1CO
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of 7 mmol (3-hydroxymethyl-6-trifluoromethyl-pyridin-2-yl)-methanol in 20 ml dichloromethane was cooled to 0° C. 0.15 mmol 4-(N,N-dimethylamino)-pyridine and 15 mmol of mesyl chloride was added, followed by careful addition of 28 mmol triethyl amine. After stirring for 1 hour at 0° C., the reaction mixture was extracted with dichloromethane, dried and concentrated. The crude mesylate was dissolved in 10 ml N,N-dimethyl formamide, treated with 21 mmol DIPEA and 9 mmol triphenyl methylamine and hold overnight at 60° C. The resulting mixture was concentrated, diluted with water and extracted 3 times with ethyl acetate. The crude compound was purified by chromatography (SiO2; ethyl acetate/n-heptane 1:4) to give the title compound as a viscous yellow oil. Yield: 37%.
Reaction SMILES: [Cl:1][C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2([OH:28])[CH2:27][CH:26]=[CH:25][CH2:24]2)=[CH:17][CH:16]=1.[N+](C([O-])=O)(C([O-])=O)=[N-].[K+].[K+].CC(O)=O>CS(C)=O.CO>[Cl:1][C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2([OH:28])[CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:19][CH:20]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CC=CC4)cc3)c(Cl)sc2[nH]c1=O
Agent: [K+]
Agent: [N-]=[N+](C(=O)[O-])C(=O)[O-]
Solvent: CS(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCCC4)cc3)c(Cl)sc2[nH]c1=O
Reaction time: 0.17 h

Procedure:
To an ambient slurry of 2-chloro-4-hydroxy-3-{4-[(1-hydroxycyclopent-3-en-1-yl)methoxy]phenyl}-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (60 mg, 0.15 mmol) and potassium diazodicarboxylate (88 mg, 0.45 mmol) in a mixture of DMSO (1.0 mL) and MeOH (1.3 mL) was slowly added a solution of AcOH (0.051 mL, 0.90 mmol) in MeOH (0.30 mL). After 10 minutes, the reaction was quenched by the addition of 1N HCl (10 mL) and EtOAc (5 mL). The layers were separated, and the aqueous was extracted with additional EtOAc (2×5 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RPLC to give the titled compound as a white solid. MS (ESI) m/e 415 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67 (m, 8H), 3.88 (s, 2H), 6.94 (d, J=8.82 Hz, 2H), 7.22 (d, J=8.82 Hz, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH3:23]>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccnc(C)c1
Reactant: CCCCC#CCCCCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1ccc(C)cc1C
Temperature: 25 °C
Yield: 84 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 2,4-lutidine (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in a vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 2,4-lutidine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (84%). 1HNMR (300 MHz, CDCl3, ppm), 9.40 (d, 1H), 7.75 (d, 1H), 7.66 (s, 1H), 4.78 (t, 3H), 2.88 (s, 3H), 2.60 (s, 3H), 2.05-2.15 (br, 4H), 1.80-2.00 (br, 2H), 1.30-1.50 (br, 10H), 0.86 (t, 3H); 13CNMR, 156.73, 153.05, 145.84, 136.61, 127.27, 80.86, 79.85, 58.12, 31.54, 30.94, 39.09, 26.17, 22.39, 22.30, 21.03, 18.96, 18.79, 14.02.
Reaction SMILES: N[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=O.[Na+].[F:19][B-](F)(F)F.[H+]>Cl.O>[F:19][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1F
Temperature: 0 °C
Yield: 79.4 %

Procedure:
3-Amino-2-naphthoic acid (40.4 g, 216 mmol) was placed in 200 mL concentrated HCl. At 0° C., the slurry was stirred vigorously using a mechanical stirring blade. To it was added a cold solution of sodium nitrite (29.8 g, 432 mmol) in 70 mL water. After completion, the cold slurry was stirred for 30 minutes at 0° C. To it was added cold tetrafluoroboric acid (48 wt. % in water, 56 mL, 432 mmol). After stirred at 0° C. for 30 minutes, the solid was filtered using a Buchner funnel. The soild cake was carefully rinsed with cold water (10 mL ×2), cold tetrafluoroboric acid (10 mL ×2) and cold ethanol (5 mL ×2). The solid was dried in vacuuo. It was then placed in 300 mL xylene and refluxed overnight. Xylene was removed on rotovap. The residue was acidified to pH 1 with aq HCl and taken into EtOAc. It was washed with brine (×2), dried, evaporated to give 3-fluoro-2-naphthoic acid (32.6 g, 78%). ES-MS: (M+H)+191.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[S:7](Cl)(=[O:9])=[O:8].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:11]1[C:16]2[C:15](=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][S:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)(=[O:9])=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1cnccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2cccnc12)c1cnccn1
Yield: 13 %

Procedure:
In a similar fashion using route 18 general procedure 27, 8-aminoqunoline (300 mg, 2.08 mmol), pyrazine-2-sulfonyl chloride 443 (482 mg, 2.7 mmol), pyridine (3 ml), DMAP (cat.) and DCM (2 ml) gave the title compound (102 mg, 13%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:25](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:26].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:25]([NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)[CH3:26]
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reaction time: 22 h
Yield: 117.3 %

Procedure:
A solution of 0.29 g (0.001 mol) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 50 ml dimethylformamide was treated with 0.05 g (0.001 mol) sodiumhydride(55%) for 15 minutes at room temperature. Then 0.22 g (0.001 mol) ethyl-p-toluenesulfonate were added and stirring was continued for 22 hours. Saturated aqueous sodiumbicarbonate was added and the mixture was extracted with dichloromethane. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 96/4 gave 0.37 g(17%) ethyl-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-amine as beige crystals. MS m/e (%): 316 (M+H+, 100).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=C[CH:9]=1.CC(C)C(=O)C(=NO)C.[F:30][C:31]([F:41])([F:40])C1C=C(C=CC=1)C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:31]([F:41])([F:40])[F:30])[CH:19]=2)[O:6][C:7]=1[CH:8]([CH3:9])[CH3:13]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=NO)C(=O)C(C)C
Product: CC(C)c1oc(-c2cccc(C(F)(F)F)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 4-methylpentane-2,3-dione-2-oxime and 3-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-isopropyl-2-(3-trifluoromethylphenyl)-oxazole.