Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][C:11]=1[F:25])[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:29]=1[C:30]([O:32][CH3:33])=[O:31].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:33][O:32][C:30]([C:29]1[C:28]([C:13]2[CH:14]=[CH:15][C:10]([C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:26])[CH3:9])=[C:11]([F:25])[CH:12]=2)=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:31]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COC(=O)c1c(Cl)cccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)c(F)c1

Procedure:
A mixture of {(R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (600 mg, 1.64 mmol, intermediate 13), methyl 2-bromo-6-chlorobenzoate (430 mg, 1.72 mmol) [CAS 685892-23-3; commercially available], tri-o-tolyl-phosphane (100 mg, 329 μmol), potassium carbonate (568 mg, 4.11 mmol) and palladium(II) acetate (18.4 mg, 82.1 μmol) in THF (20.0 ml) and water (1.18 ml) was stirred at room temperature over night. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined extracts were washed with water and brine, dried with Na2SO4 and concentrated in vacuo. The remaining residue was purified by chromatography (silica gel; DCM/EtOAc 100:0-90:10) and the title compound was obtained as colorless oil (385 mg, 58%). MS: 466.1 [M−H+OAc]−.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>Cl>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[S:20]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:33])=[O:5])=[CH:12][CH:11]=2)[CH2:19][CH2:18]1)(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(NC2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.9 %

Procedure:
A solution of (9) (0.05 g, 0.12 mmol) in HCl (2 mL, 4M in 1,4-dioxane) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was then concentrated to give a pale yellow oily residue (0.03 g, 68%); 1H NMR (DMSO) δ 8.44 (s, 1H), 8.20 (m, 1H), 8.09 (m, 1H), 7.72 (m, 4H), 7.57 (d, 2H, J=5.7), 6.50 (d, 2H, J=6.8), 3.60 (m, 2H), 3.25 (m, 1H), 2.55 (m, 2H), 1.93 (d, 2H, J=11.9), 1.45 (m, 2H); 13C NMR (DMSO) δ 167.4, 151.3, 134.4, 132.7, 131.9, 131.1, 129.3, 129.0, 128.6, 127.9, 122.9, 111.2, 47.2, 45.0, 30.6; HRMS (FAB) m/z 411.1366 (M+H)+ (C22H22N2O4S requires 411.1379); Anal. (C22H22N2O4S·2HCl·2H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1c[nH]c(Sc2cc(Cl)cc(Cl)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cc(Cl)cc(Cl)c2)c1

Procedure:
Methyl 5-(3,5-dichlorophenylthio)pyrrole-3-carboxylate (2.5 g.) was combined with 25 ml. of methanol and 25 ml. of 1 N sodium hydroxide and refluxed for 3 hours. The methanol was allowed to evaporate, the aqueous residue diluted with approximately one volume of water and washed twice with ether. The aqueous phase was acidified with conc. hydrochloric acid and the product extracted into ethyl acetate. The two ethyl acetate extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to crude product (1.84 g., m.p. 169°-172° C.). Recrystallization from chloroform afforded purified 5-(3,5-dichlorophenylthio)pyrrole-3-carboxylic acid (1.3 g., m.p. 175°-177° C.).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:35])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:26][N:27]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:35])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:24][C:25]([CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:26][N:27]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(CN3CCCCC3)s2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)c1ccc(-c2ncc(CN3CCCCC3)s2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
N-(2-t-butoxycarbonylaminophenyl)-4-[5-(piperidin-1-ylmethyl)-1,3-thiazol-2-yl]benzamide (Method 51, 271 mg, 0.54 mmol) was suspended in 1,4 dioxane (4 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (4 ml) added. The reaction mixture was stirred at ambient temperature for 17 hours. The resultant precipitate was collected by filtration, washed with diethyl ether and air dried to yield the title compound as its hydrochloride salt. The crude solid was purified using an Oasis MCX column, eluting with methanol/dichloromethane (0-100%) then 2M ammonia in methanol/methanol (0-20%) to give the title compound as its free base (119 mg, 56%); NMR Spectrum: (DMSO-d6) 1.40 (m, 2H), 1.50 (m, 4H), 2.41 (m, 4H), 3.74 (s, 2H), 4.94 (s, 2H), 6.61 (t, 1H), 6.80 (d, 1H), 6.99 (t, 1H), 7.18 (d, 1H), 7.80 (s, 1H), 8.06 (d, 2H), 8.09 (d, 2H), 9.78 (s, 1H); Mass Spectrum: M+H+ 402.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:17]([CH3:21])[C:18](=[O:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[F:22][C:23]([F:28])([F:27])[C:24](O)=O>>[CH3:21][N:17]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:10][CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:24]([C:23]([F:28])([F:27])[F:22])=[N:2][C:3]=2[CH:4]=1)[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(N)c1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: CC(=O)N(C)c1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Yield: 90 %

Procedure:
A solution of N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N-methylacetamide hydrochloride (2.77 g, 10 mmol) in trifluoroacetic acid (60 mL) was heated to reflux for 18 h. After evaporation of the solvent, the residue was dissolved in EtOAc (200 mL), washed with 2N NaOH (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc on silica gel to give 3.18 g (90%) of a white solid as the title compound. MS (ESI) (M+H)+=356.02.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:30][C:28]([F:29])([F:31])[O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][O:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[N:6]([CH2:5][C:4]([OH:32])=[O:3])[CH:7]=[CH:8]3)=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cn1ccc2cccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)c21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2cccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)c21

Procedure:
In analogy to the procedure described for example 1 e], {7-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as brown liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.C([SnH2][C:18]1[CH:23]=[CH:22][N:21]=[N:20][CH:19]=1)(C)(C)C.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1[CH:19]=[CH:18][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=3[CH:12]=2)=[CH:22][N:21]=1
Reactant: OCc1cc2cc(Br)ccc2o1
Reactant: CC(C)(C)[SnH2]c1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cc2cc(-c3ccnnc3)ccc2o1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a solution of (5-bromo-benzofuran-2-yl)-methanol (1.6 g, 3.7 mmol) and 4-tert-butylstannanyl-pyridazine (1 g; 4.4 mmol) in 15 mL dry toluene, was added tetrakis(triphenylphosphine)palladium (0) (130 mg). The mixture was stirred at 95° C. overnight. After allowing the mixture to come to room temperature, the solution was poured into water, extracted, dried over MgSO4, and filtrated to afford 2.4 g of crude product that was further purified by chromatography to afford (5-pyridazin-4-yl-benzofuran-2-yl)-methanol.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH2:11])=[O:10])C)=[O:5])[CH3:3]>CO>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][CH2:7][C:9]([NH2:11])=[O:10])=[O:5])[CH2:3][CH2:3][CH2:2][CH2:4][NH2:6]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(N)=O
Solvent: CO
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O

Procedure:
Z-L-Ala-L-Ala-NH2 (12) (Katakai et al., Macromolecules, 6:827-831 (1973), which is hereby incorporated by reference): 1H NMR (DMSO-d6) δ1.20 (2×d, J=7 Hz, 6H, 2×CH3), 4.10, 4.20 (m, 2H, 2×NHCHCO), 5.00 (s, 2H, OCH2Ph), 7.20-7.40 (m, 5H, Ph); 13C NMR (DMSO-d6) δ18.1, 18.4, 47.9, 50.1, 65.4, 127.7, 128.4, 137.0, 155.8, 172.0. 174.1. HRMS (FAB+) MH+ calcd 294.1454 found 294.1457. [α]25D=−20.4 (c 0.77, MeOH).
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[C:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:14]([C:3]2[C:2]([F:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([F:13])[C:4]=2[CH2:5][OH:6])[CH2:15]1)(=[O:22])[CH3:21]
Reactant: NC1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NC1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)C1
Reaction time: 0.17 h

Procedure:
To 3,6-difluoro-2-(3-amino-1-pyrrolidinyl)-5-nitrobenzyl alcohol (43 mg) is added acetic anhydride (0.5 ml) at room temperature. The mixture is stirred at the same temperature for 10 minutes, and the reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is washed with water and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate, and then solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane→methanol:dichloromethane=1:12) and then recrystallized from dichloromethane to give 2-(3-acetylamino-1-pyrrolidinyl)-3,6-difluoro-5-nitrobenzyl alcohol (40 mg), as yellow prisms, m.p. 142.5°-143.5° C.
Reaction SMILES: [O:1]=[C:2]1CCC[C:8]2NC(=S)C(C#N)=C[C:3]1=2.[NH2:15][C:16]1[CH2:25][CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[C:18](=[O:26])[CH:17]=1.C(OC)(=O)C#C>>[NH:15]1[C:16]2[CH2:25][CH:24]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[C:18](=[O:26])[C:17]=2[CH:8]=[CH:3][C:2]1=[O:1]
Reactant: N#Cc1cc2c([nH]c1=S)CCCC2=O
Reactant: NC1=CC(=O)C2CCCCC2C1
Agent: C#CC(=O)OC
Product: O=C1c2ccc(=O)[nH]c2CC2CCCCC12

Procedure:
In close analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092), 3-amino-4a,5,6,7,8,8a-hexahydro-4H-naphthalen-1-one was reacted with methyl propiolate to give the title compound as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+].O.[Sn]>C1COCC1.C(Cl)Cl.C(OCC)(=O)C.CO>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[CH2:13][CH2:12][CH2:11][C:5]3([CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[C:3]2=[O:2])=[CH:16][CH:17]=1
Reactant: COC(=O)C1(CCCNc2ccc(Br)cc2)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Sn]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1N(c2ccc(Br)cc2)CCCC12CCOCC2
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
To a clear solution of 4-[3-(4-Bromo-phenylamino)-propyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (0.74 g, 2.08 mmol) in THF (25 mL) was added a solution of 1.0 mL of potassium t-butoxide (1M in THF) at r.t. (water bath at rt). The clear solution turned a little bit cloudy. After 15 min, TLC (5% MeOH in DCM) showed the reaction is complete (spot to spot), LC/MS detected the product peak. The reaction was cooled tin an ice-water bath, diluted with 25 mL of ethyl acetate, quenched with 10 mL of water. The two layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined EtOAc extracts were washed with brine, and concentrated on rotavap to yield a crude product as a slightly yellow solid. This material was loaded onto a 25-g of silica gel column, eluted with DCM and 5% MeOH in DCM to get 0.64 g (86% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH2:8][C:7]([CH2:10][CH3:11])([CH3:9])[NH:6][C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)N=1)[CH3:2].[Br-].[NH4+].[OH2:19]>CO>[CH2:10]([C:7]1([CH3:9])[CH2:8][C:3](=[O:19])[CH:1]([CH3:2])[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:6]1)[CH3:11]
Reactant: CCC1=NC2(CCCCC2)NC(C)(CC)C1
Reactant: O
Agent: [Br-]
Agent: [NH4+]
Solvent: CO
Product: CCC1(C)CC(=O)C(C)C2(CCCCC2)N1

Procedure:
11.1 g of the 2,4-diethyl-4-methyl-1,5-diazaspiro[5.5]undec-1-ene thus obtained and 2.5 g of ammonium bromide were dissolved in 70 ml of methanol. 45 ml of water were added to the solution, with stirring. The mixture was then stirred at room temperature for 8 hours. Methanol was removed by evaporation under reduced pressure and the residue was then distilled under reduced pressure, giving 7.4 g of the title product, bp 119°-122° C./1.5 mmHg.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][C:10]2([CH2:15][CH3:16])OCCO2)=[C:4]([NH2:17])[N:3]=1.Cl>>[CH3:1][C:2]1[NH:3][C:4]2[NH:17][C:10]([CH2:15][CH3:16])=[CH:9][C:5]=2[C:6](=[O:8])[N:7]=1
Reactant: CCC1(Cc2c(N)nc(C)nc2O)OCCO1
Agent: Cl
Product: CCc1cc2c(=O)nc(C)[nH]c2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 2-methyl-6-amino-5-(2-ethyl-1,3-dioxolan-2-ylmethyl)-4-pyrimidinol (5.50 g, 22.9 mmol) was combined with 172 mL of 0.2 M HCl and stirred at ambient temperature for 18 hours. The solids were collected by filtration, washed with 40 mL of water and dried in vacuo (40° C., 10 torr) to 3.70 g (91%) of 1,7-dihydro-2-methyl-6-ethyl-4H-pyrrolo[2,3-d]pyrimidin-4-one as a tan solid. nmr (500 MHz, dmso-d6) δ1.18 (t, J=7.5 Hz, 3H), 2.26 (s, 3H), 2.57 (q, J=7.5 Hz, 2H), 6.04 (s, 1H), 11.42 (s, 1H), 11.57 (s, 1H)
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[CH:25]=[CH:24][C:18]3[O:19][C:20]([F:23])([F:22])[O:21][C:17]=3[CH:16]=2)=[O:14])=[CH:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:23][C:20]1([F:22])[O:19][C:18]2[CH:24]=[CH:25][C:15]([C:13]([C:10]3[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=3)=[O:14])=[CH:16][C:17]=2[O:21]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc3c(c2)OC(F)(F)O3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccc(O)cc1)c1ccc2c(c1)OC(F)(F)O2
Yield: 99.2 %

Procedure:
A solution of 11.4 grams (0.029 mole) of [4-[(1,1dimethylethyl)dimethylsilyloxy]phenyl](2,2-difluoro-1,3-benzodioxol-5-yl) ketone in 50 mL of tetrahydrofuran was stirred, and 13.7 grams (0.044 mole) of tetrabutylammonium fluoride was added. Upon completion of addition the reaction mixture was stirred for ten minutes. After this time the reaction mixture was washed in turn with an aqueous solution saturated with ammonium chloride, water, aqueous dilute hydrochloric acid, and an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 8.0 grams of 4-hydroxyphenyl (2,2-difluoro-1,3-benzodioxol-5-yl) ketone. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][C:8]=2[C:16]([F:17])([F:18])[F:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1ccc(C2=CCCCC2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Yield: 95.9 %

Procedure:
4-(1-Cyclohexen-1-yl)-3-(trifluoromethyl)benzamide (D66) (850 mg, 3.16 mmol) was dissolved in methanol (63 ml) and hydrogenated using an H-Cube, using palladium on carbon at 40° C. with a flow rate of 2 mL/min. The solvent was removed in vacuo to give the title compound as a white solid (822 mg). δH (CDCl3, 400 MHz): 8.08 (1H, d), 7.94 (1H, dd), 7.52 (1H, d), 6.54 (2H, brs), 2.97 (1H, m), 1.90-1.75 (5H, m), 1.50-1.22 (5H, m). MS (ES): C14H16F3NO requires 271; found 272 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:12]1[C:13]2[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31][C:14]=2[N:15]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][N:27]=[C:26]3[CH3:30])=[CH:21][CH:20]=2)[N:17]=1.Cl>CO>[CH3:30][C:26]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16]3[N:17]=[C:12]([N:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH2:11][C@H:3]4[CH2:2][OH:1])[C:13]4[CH2:34][NH:33][CH2:32][CH2:31][C:14]=4[N:15]=3)=[CH:20][CH:21]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(N4c5ccccc5C[C@H]4CO)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N4c5ccccc5C[C@H]4CO)n2)CNCC3)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
(S)-tert-Butyl 4-(2-(hydroxymethyl)indolin-1-yl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (65.3 mg, 0.12 mmol) was dissolved in methanol (3 mL). Hydrochloric acid (9.69 μL, 0.12 mmol) was added and the reaction mixture was stirred at 75° C. for 1 h. The solvent was evaporated under reduced pressure and the crude was used as such in the subsequent step. MS (ES+) m/z 454.3 (M+H)+
Reaction SMILES: [N:1]([CH:4]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+]=[N-]>CCO.[Pd]>[O:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[CH:4]([NH2:1])[CH2:5][CH2:6]1
Reactant: [N-]=[N+]=NC1CCOc2ncccc21
Agent: [Pd]
Solvent: CCO
Product: NC1CCOc2ncccc21
Reaction time: 3 h

Procedure:
A mixture of 4-azido-3,4-dihydro-2H-pyrano[2,3-b]pyridine (3.0 mmol) and Pd/C (10 mol %) in 12 mL EtOH was stirred under a H2 atmosphere. After 3 h, the mixture was filtered over a pad of Celite, washed with EtOH and concentrated in vacuo to obtain the title compound as colorless oil;
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:29])[C:6]([CH3:30])=[C:5]([O:31][CH3:32])[CH:4]=1.[F:33]/[C:34](=[CH:43]\[CH:44]=[C:45](/[CH3:48])\[CH:46]=O)/[C:35](/[CH3:42])=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1OC1CC>CCOCC>[Cl:2][C:3]1[C:8](/[CH:9]=[CH:48]/[C:45](/[CH3:46])=[CH:44]/[CH:43]=[C:34](\[F:33])/[C:35](/[CH3:42])=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:7]([CH3:29])[C:6]([CH3:30])=[C:5]([O:31][CH3:32])[CH:4]=1
Reactant: CCOC(=O)/C=C(C)/C(F)=C/C=C(\C)C=O
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: CCC1CO1
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)/C=C(C)/C(F)=C/C=C(C)/C=C/c1c(Cl)cc(OC)c(C)c1C
Yield: 35 %

Procedure:
A mixture of 6.0 g. (12.46 mmol) of 6-chloro-4-methoxy-2,3-dimethylbenzyl triphenylphosphonium chloride and 2.71 g. of ethyl (E,Z,E)-4-fluoro-3,7-dimethyl-8-oxo-2,4,6-octatrienoate in 15 ml. of 1,2-butylene oxide was heated at 110° C. in a sealed tube for 60 hours. The resulting mixture was worked up with ether in the usual manner to give 13.53 g. of crude product. This material was chromatographed on 300 g. of silica gel. Elution with 1:4 ether-petroleum ether yielded 4.65 g. of yellow crystals. Recrystallization of this material from methylene chloride-petroleum ether afforded 1.67 g. (35% yield) of pure ethyl (E,Z,E,E)-9-(6-chloro-4-methoxy-2,3-dimethylphenyl)-4-fluoro-3,7-dimethyl-2,4,6,8-nonatetraenoate as yellow crystals, mp. 126°-128° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C(O)=O)[C:2]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.N1C=CC(C(O)=O)=CC=1C1C=C(C(O)=O)C=CN=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(O)c1cccnc1-c1ccccn1
Agent: O=C(O)c1ccnc(-c2cc(C(=O)O)ccn2)c1
Product: c1ccc(-c2ccccn2)nc1

Procedure:
Fluorescent bipyridyl indicators are prepared using synthetic methods that are entirely analogous to those described in Example 3, excepting that the starting material is a bipyridyl carboxylic acid such as 2,2'-bipyridine-4,4'-dicarboxylic acid (Aldrich Chemical Company).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH2:11])[CH2:10][CH2:9]1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:16](Cl)=[O:17].O>O1CCCC1>[CH:8]1([NH:11][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:13]([CH3:12])[CH:14]=2)[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: Cc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NC2CC2)ccc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 76.2 %

Procedure:
3.35 g (33 mmol) of triethylamine was added to a solution containing 1.65 g (29 mmol) of cyclopropylamine in 50 ml of tetrahydrofuran, then 5.0 g (28 mmol) of 3-methyl-4-nitrobenzoyl chloride was added dropwise while cooled with iced water. The reaction mixture was allowed to room temperature and after stirred for 12 hours, poured into iced water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 4.7 g of the desired compound. This was used in the next reaction without being purified.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C@:7]2([CH3:15])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:14])=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC([C@](O)(C)C(O)=O)=CC=1.C1C=CC([C@H](N)CO)=CC=1>>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([CH3:15])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:14])=[CH:3][CH:2]=1
Reactant: C[C@@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Agent: C[C@](O)(C(=O)O)c1ccc(-c2ccccc2)cc1
Agent: N[C@H](CO)c1ccccc1
Product: C[C@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Yield: 19 %

Procedure:
(R)-(-)-5-[(1,1'-Biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone was prepared in an analogous manner as described for (S)-(+)-5-[(1, 1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with 1.9 g (5.0 mmol) of the diastereomerically pure salt of (R)-(-)-2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionic acid and (S)-(+)-phenylglycinol to provide 280 mg (19% yield) of (R)-(-)-5-[(1,1'-biphenyl)-4-yl]-3,4 -dihydroxy-5-methyl-2(5H)-furanone as a white crystalline material: mp 197-199° C. dec. (CHCl3 /hexanes); [α]25D -182° (c=1.42; MeOH); 1H NMR (acetone-d6) δ 7.65-7.41 (m, 9H), 1.89 (s, 3H). Anal Calcd for C17H14O4 +0.25 H2O: C, 71.20; H, 5.10. Found: C, 71.19; H, 4.74.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:10]=[C:9]([C:11](=O)[CH2:12]Br)[CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH:2]([OH:1])[CH2:3][OH:4])[N:10]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: O=C(CBr)c1cccc(C(O)CO)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)CO)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(1,2-dihydroxyethyl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(1,2-dihydroxyethyl)-2-pyridyl]thiazole.