Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[C:6]([OH:14])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
N,O-dimethyl hydroxyl amine hydrochloride (4.393 g, 45.037 mmol) was added to a stirred solution of benzoic acid (5.0 g, 40.943), EDC.HCl (9.418 g, 49.132) and N-methyl morpholine (4.141 g, 40.943 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at rt for 4 h. After completion of the reaction, the reaction mixture was concentrated. Diethyl ether was added and the mixture was extracted with water and brine. The organic layer was dried over Na2SO4 and filtrated. Concentration of the organic layer furnished the title compound as a colorless liquid (4.933 g, 73%). [1H-NMR (CDCl3, 300 MHz) δ 7.72-7.64 (m, 2H), 7.52-7.36 (m, 3H), 3.58 (s, 3H), 3.38 (s, 3H); HPLC RtA=6.281 min. (98%); LCMS RtA=0.38 min; [M+H]+=166.1]
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:29]=[N:28][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:14](=[O:15])[C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:29]=[N:28][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:14](=[O:15])[C:9]=3[C:8]=2[CH:45]([C:44]2[CH:47]=[CH:48][C:41]([F:40])=[CH:42][CH:43]=2)[OH:46])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3ccc(Cl)cc3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(F)cc3)c(Oc3ccc(Cl)cc3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a solution of 6-(4-chlorophenoxy)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (110 mg, 0.25 mmol) in THF (5 mL) at −78° C. was added LDA (2.0 M in THF, 0.63 mL, 1.25 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-fluorobenzaldehyde (62 mg, 0.50 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h, quenched with sat. aq. NH4Cl (5 mL) then diluted with EA (30 mL) and water (30 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by chromatography eluted with PE/EA (7:1) to give 6-(4-chlorophenoxy)-5-((4-fluorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (55 mg, 40% yield) as a solid. LCMS: [M++Na] 592 and TR=3.372 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1)(=[O:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)n1ccc2ccc([N+](=O)[O-])cc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56.2 %

Procedure:
To a solution of 6-nitro-1H-indole (0.250 g, 1.54 mmol) in dry THF (15.4 mL) at −78° C. under nitrogen was added sodium bis(trimethylsilyl)amide (1.850 mL, 1.850 mmol) dropwise via syringe. The resulting solution was stirred for 20 minutes at −78° C., followed by addition of methanesulfonyl chloride (0.14 mL, 1.85 mmol) dropwise via syringe. Following the addition, the cooling bath was removed, and the mixture was allowed to warm to room temperature. After 1 hour, the suspension was filtered, and the resulting solid was taken up in 10 mL of aqueous MeOH and heated to reflux. The hot mixture was filtered to afford a light yellow solid which was dried in vacuo, furnishing Intermediate 64A (0.208 g, 56% yield) as a light yellow solid. HPLC: Rt=3.160 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=241.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d, J=2.01 Hz), 8.18 (1H, dd, J=8.81, 2.01 Hz), 7.98 (1H, d, J=3.78 Hz), 7.92 (1H, d, J=8.81 Hz), 7.05 (1H, d, J=3.78 Hz), 3.55-3.66 (3H, m).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[C:23]([CH3:24])=[C:22]([NH:25][CH:26]2[CH2:28][CH2:27]2)[N:21]2[N:29]=[CH:30][C:31]([CH:32]=O)=[C:20]2[N:19]=1)[C:12]#[N:13].N1CCCCC1>C(O)C.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[C:23]([CH3:24])=[C:22]([NH:25][CH:26]2[CH2:27][CH2:28]2)[N:21]2[N:29]=[CH:30][C:31]([CH:32]=[C:7]3[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]3)=[C:20]2[N:19]=1)[C:12]#[N:13]
Reactant: Cc1c(Nc2ccc(C#N)cc2Cl)nc2c(C=O)cnn2c1NC1CC1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(Nc2ccc(C#N)cc2Cl)nc2c(C=C3NC(=O)NC3=O)cnn2c1NC1CC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 57.8 %

Procedure:
Hydantoin (2.7 mg, 0.027 mmol) and 3-chloro-4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (10 mg, 0.027 mmol) were dissolved in ethanol (0.4 mL) along with piperidine (3 uL, 0.03 mmol). The reaction was heated at 80° C. After 10 hours, the reaction was cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The bright yellow solid was dried in vacuo to give 3-chloro-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-6-methylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (7 mg, 58% yield). LCMS (M+1=449)
Reaction SMILES: [CH3:1][C:2]([CH:5]1[C:11](OC)=[N:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH3:1][C:2]([CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1=[NH:15])([CH3:4])[CH3:3]
Reactant: [Cl-]
Reactant: COC1=NCCCCC1C(C)(C)C
Reactant: [NH4+]
Solvent: CO
Product: CC(C)(C)C1CCCCNC1=N
Product: Cl
Yield: 63.3 %

Procedure:
The product of EXAMPLE 99 (551 mg, 2.7 mmol) in 10 mL of MeOH was reacted with ammonium chloride (145 mg, 2.7 mmol) by the method of EXAMPLE 27 to yield 350 mg of the crude title material.
Reaction SMILES: [I:1]Cl.[N-:3]=[N+:4]=[N-:5].[Na+].[OH:7][CH2:8][CH:9]([CH2:22][OH:23])[CH2:10][CH2:11][N:12]1[CH:19]=[C:18]([CH:20]=[CH2:21])[C:16](=[O:17])[NH:15][C:13]1=[O:14].C(Cl)(Cl)Cl.CO>C(#N)C>[OH:7][CH2:8][CH:9]([CH2:22][OH:23])[CH2:10][CH2:11][N:12]1[CH:19]=[C:18]([CH:20]([N:3]=[N+:4]=[N-:5])[CH2:21][I:1])[C:16](=[O:17])[NH:15][C:13]1=[O:14]
Reactant: C=Cc1cn(CCC(CO)CO)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Reactant: ClI
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CO
Product: [N-]=[N+]=NC(CI)c1cn(CCC(CO)CO)c(=O)[nH]c1=O
Temperature: 0 °C
Yield: 21.3 %

Procedure:
Iodine monochloride (50 mg, 0.3 mmol) was added slowly with stirring during a five minute period to a suspension of sodium azide (72 mg, 1.1 mmol) in dry acetonitrile (10 ml) at ice-bath temperature with stirring. This mixture was stirred for a further 5 min., a solution of 20 (66 mg, 0.275 mmol) in dry acetonitrile (40 ml) was added, the reaction mixture was maintained at 0° C. for 30 min. with stirring. The resulting red-brown colored reaction mixture was poured onto ice cold water (25 ml), the mixture was extracted with ethyl acetate (3×50 ml) and the ethyl acetate extract was washed with 5% aqueous sodium thiosulfate (30 ml). Drying the colorless ethyl acetate fraction (Na2SO4), removal of the solvent in vacuo and purification of the residue obtained by elution from a silica gel column using chloroform:methanol (90:10, v/v) as eluent afforded 21c (24 mg, 21%) as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].Cl(O)(=O)(=O)=O.[C:21](O)(=O)C>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: CC(=O)O
Reactant: Cc1cc(C(=O)CCC(=O)O)ccc1F
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)CCCc1ccc(F)c(C)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
The compound obtained in (1) above (172 gm) was dissolved into 700 ml of acetic acid. To the solution were added 10 ml of 40% perchloric acid and 30 gm of 10% palladium-on-carbon to effect catalytic hydrogenation under 6 atm. The catalyst was removed by filtration and acetic acid was evaporated. Upon the addition of 2 l of water, the residue was extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and 1 l of methanol was added to the residue. After cooling to 0° C., 269 gm of thionyl chloride was slowly dropped to the solution, followed by the addition of 10 ml of dimethylformamide. The mixture was stirred for 12 hours at room temperature, the reaction product was concentrated, and extracted with chloroform. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 153 gm of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH:7]([N:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl.C1COCC1>[CH2:17]([N:14]([CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]([NH:1][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([F:24])=[CH:26][C:27]=1[C:34]([F:37])([F:35])[F:36])[C:3]([O:5][CH3:6])=[O:4])[CH:15]=[O:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)C(N)C(c1ccccc1)N(C=O)Cc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(c1ccccc1)N(C=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
1.4 g (0.0052 mol) of methyl 2-amino-3-(N-benzyl-N-formylamino)-3-phenylpropionate were dissolved in methylene chloride, and 1.0 g (0.0052 mol) of 4-fluoro-2-trifluoromethylbenzoic acid and 1.0 g (0.010 mol) of triethylamine in THF were added. At 0-5° C., 1.3 g (0.0052 mol) of bis(2-oxo-3-oxazolidinyl)phosphoryl chloride were added. After 2 h at 0° C., the mixture was stirred at room temperature for 15 h. The solvents were removed and the residue was taken up in ethyl acetate, washed and dried. Chromatographic purification (silica gel column, cyclohexane/ethyl acetate) gave 0.65 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].[C:7]1([CH:17]([NH2:19])[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C(#N)C>CO>[OH:1][CH:2]([PH:4](=[O:5])[O-:6])[CH3:3].[C:7]1([CH:17]([NH3+:19])[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(N)c1cccc2ccccc12
Reactant: CC(O)[PH](=O)O
Solvent: CO
Solvent: CC#N
Product: CC(O)[PH](=O)[O-]
Product: CC([NH3+])c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Crude α-hydroxyethylphosphinic acid (57.7 g; 0.524 mol) prepared as in Example 1 was dissolved in methanol (290 ml). α-Naphthylethylamine (90.2 g; 0.575 mol) was added thereto at a temperature of not more than 50° C. while stirring. The reaction mixture was kept at a temperature of 25° to 30° C. for 30 minutes, followed by distillation of methanol to give a foamy substance. To the foamy substance, methanol (60 ml) and acetonitrile (600 ml) were added, followed by vigorous stirring, whereby crystals were precipitated. To the resultant mixture, methanol (130 ml) was added, followed by heating with reflux. After cooling, precipitated crystals were collected by filtration to give (±)-α-naphthylethylammonium α-hydroxyethylphosphinate (Compound No. 22) (56.0 g). M.P., 164° C. Yield, 37.8%. The mother liquor was concentrated, and the residue was recrystallized from a mixture of acetonitrile (400 ml) and methanol (105 ml) to give (±)-α-naphthylethylammonium α-hydroxyethylphosphinate (23.0 g). The thus prepared (±)-α-naphthylethylammonium α-hydroxyethylphosphinate (73.6 g; 0.2616 mol) was dissolved in distilled water (500 ml), cation exchange resin (Dowex 50W ×8H+ type; 600 g) was added thereto, and the resultant mixture was stirred for 40 minutes. After separation of the resin, the filtrate was concentrated to give pure α-hydroxyethylphosphinic acid (Compound No. 1) (27.0 g). Yield, 93.8%. No peak due to any impurity was recognized by NMR.
Reaction SMILES: [CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>CO>[CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:6]1[OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1O
Yield: 77.2 %

Procedure:
To a solution of 2,2-dibutyl-3,4-dihydro-5-(2-quinolylmethoxy)-1(2H)-naphthalenone (500 mg) in methanol (20 ml) was added sodium borohydride (68 mg) with stirring in an ice bath. The mixture was stirred for half an hour in an ice bath and then sodium borohydride (136 mg) was added thereto at the same temperature. The solution was stirred for 1.5 hours at ambient temperature, followed by the addition of sodium borohydride (68 mg). The mixture was stirred at ambient temperature for half an hour and then poured into water with stirring in an ice bath. The separated solid was collected by filtration, washed with water (50 ml), dried, and recrystallized from methanol to yield 2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphthol (388 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl.[CH3:13]O>C(OCC)C>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(Br)cc1C

Procedure:
4-Bromo-2-methylbenzoic acid (5.0 g, 23 mmol) was suspended in methanol (30 mL). To the mixture was added a solution of HCl in diethylether (1.0M, 30 mL). The mixture was refluxed for 24 hours and concentrated to dryness. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the desired compound (5.5 g) as a brown oil.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:13][N:9]([CH2:10][CH2:11][CH2:12]1)[CH2:8][CH2:7][CH2:6]2)=O.[NH3:14]>CO.C[O-].[Na+].CO>[N:9]12[CH2:13][C:5]([C:3]([NH2:14])=[O:2])([CH2:12][CH2:11][CH2:10]1)[CH2:6][CH2:7][CH2:8]2
Reactant: COC(=O)C12CCCN(CCC1)C2
Reactant: N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)C12CCCN(CCC1)C2
Temperature: 150 °C
Yield: 38 %

Procedure:
A solution of 1-azabicyclo[3.3.1]nonane-5-carboxylic acid methyl ester (1.83 g, 10 mmol) in ammonia (50 mL) and methanol (20 mL) was sealed in a bomb and heated at 120°-130° C. for 36 hours (gas chromatography indicated that the reaction was incomplete). Three drops of 25% sodium methoxide/methanol were added, and the mixture was heated at 130° C. for 21 hours and at 150° C. for 72 hours, at which time the reaction was essentially complete. The solution was concentrated in vacuo and the residue was partitioned between 1.25 N sodium carbonate (50 mL) and methylene chloride (75 mL). The organic layer was separated and the aqueous solution was extracted with methylene chloride (2×40 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo, and recrystallized from acetonitrile to afford 0.64 g (38%) of pale brown solid: mp 172.5°-175.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=[O:20])[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)OC(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetate (124.5 g, 321.3 mmol) was dissolved in THF (1,150 ml) and MeOH (1,900 ml), and an aqueous 6 M NaOH solution (1,300 ml) was added. The reaction mixture was stirred at room temperature for 1 hour and the organic solvents were then distilled off. The residue was taken up in aqueous 6 M HCl (2,000 ml) at 0° C. and the mixture was extracted with methylene chloride (2×1,000 ml). The combined organic phases were dried, filtered and concentrated to dryness in vacuo. The yield was 103.5 g (97%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([OH:31])[CH:25]=[CH:26][CH:27]=2)[N:22]=1.[CH2:32](O)[CH2:33][CH2:34][OH:35].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[NH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: OCCCO
Reactant: Nc1ccc2cccc(O)c2n1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc2cccc(OCCCO)c2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 100 mL round bottom flask equipped with a stirring bar and a pressure equalized dropping funnel, under N2, was charged with 0.652 g (2 equiv) PPh3, 0.200 g (1.25 mmol) of 2-amino-8-hydroxyquinoline and 10 mL of anhydr. THF. After stirring for 10 min, 1.8 mL of 1,3-propanediol (20 equiv) was added in one portion. The reaction mixture was then cooled to 0° C. and 0.43 g (1.5 equiv) of DBAD in 15 mL THF was added dropwise over 10 minutes. The reaction was allowed to slowly warm to room temperature and stirring was maintained for 8 h. Then, 0.652 g (2 equiv) of PPh3 was added, the reaction mixture was cooled to 0° C. and 0.431 g (1.5 equiv) of DBAD in 15 mL THF was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 12 h. The solution was evaporated in vacuo, the residue was dissolved in DMA (25 mL) and MP-TsOH resin (Argonaut Technologies, Inc., 4.5 g) was added. The resulting suspension was agitated at room temperature for 12 h. The supernatant was subsequently drained and the resin was washed with DMA (2×20 mL), MeOH (2×20 mL) and DMA (20 mL). The washed resin was treated with a mixture of 2 N NH3 in MeOH (15 mL) and DMA (5 mL) at room temperature for 1 h. The solution was drained and the basic wash was repeated two more times. Filtered solutions were combined. The resin was washed with MeOH (20 mL), DMA (20 mL), MeOH (20 mL), DMA (20 mL) and MeOH (20 mL). The washes were combined with the previously collected solutions and evaporated in vacuo. The resulting crude material was purified by silica gel column chromatography (20:1 EtOAc/MeOH+2% TEA) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.87 (d, 1H), 7.29 (dd, 1H), 7.17 (t, 1H), 7.12 (dd, 1H), 6.72 (d, 1H), 4.34 (t, 2H), 3.99 (t, 2H), 2.12 (m, 2H), MS (DCI/NH3) m/z 219 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Yield: 90 %

Procedure:
This step was carried out using the procedure described in Tetrahedron Letters 30 (39), 1989, 5193-5196. A 0.5 M solution of A1 in acetone was treated with K2CO3 (1.3 eq.) and Me2SO4 (1.2 eq.) and the mixture was refluxed 6 h. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. The residue was dissolved in Et2O and washed with sat. aq. NaHCO3 solution, and brine, then dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with 20-100% EtOAc/petroleum ether to give the title compound in 90% yield. 1H NMR (300 MHz, CDCl3, 300K) δ 7.35 (5H, m), 5.17 (2H, m), 4.77-4.50 (2H, m), 4.10-3.85 (1H, m), 3.74 (1.5H, s), 3.64 (1.5H, s), 3.30 (1H, m), 3.10 (1H, dd, J 13.6, 4.4), 2.86 (1H, m), 1.45 (9H, s). MS (ES+) C19H26N2O6 requires 378, found: 401 (M+Na)+.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].C([Li])CCC.[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]([CH:26]=[O:27])=[C:21]2[CH:20]=[CH:19][CH:18]=1.O>O1CCCC1.CCOCC>[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]([CH:26]([OH:27])[C:3]#[C:2][CH2:1][O:4][CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][O:6]3)=[C:21]2[CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: C#CCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OC(C#CCOC1CCCCO1)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a cold (−78° C.) solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (0.5 mL, 3.6 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.05 mL, 1.6 M in hexanes, 3.3 mmol) dropwise. The reaction mixture was allowed to warm to 0° C., then cooled to −78° C. A separate solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (200 mg, 0.73 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C. The alkynyllithium solution was added to the aldehyde solution via canula. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added followed by ether. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ethyl acetate) provided 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-4-(tetrahydro-2H-pyran-2-yloxy)-2-butyn-1-ol (301 mg, 99%) as a mixture of diastereomers. 1H NMR (CDCl3) δ 8.00 (d, 1H), 7.79 (m, 2H), 7.17 (m 3H), 6.99 (m, 1H), 5.79 (s, 1H), 4.81–4.74 (m, 1H), 4.39–4.25 (m, 2H), 3.81 (m, 1H), 3.52 (m, 1H), 3.15 (broad, 1H), 1.90–1.48 (m, 6H); 19F NMR (CDCl3) δ −113.01; MS m/z 437 (M+Na+).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH3:22])[OH:19])[CH3:9].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][Br:29])=[CH:26][CH:25]=1>>[Br-:29].[O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][SH+:21][CH2:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([CH3:28])=[CH:26][CH:25]=1)[OH:19])[CH3:9]
Reactant: Cc1ccc(CBr)cc1
Reactant: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Product: COC1C(O)CCC(O)(C[SH+]CCc2ccc(C)cc2)C1C1(C)OC1CC=C(C)C
Product: [Br-]
Yield: 63.5 %

Procedure:
As in Example 54, 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) was allowed to react with 4-methylbenzyl bromide (1.12 g) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(4-methylbenzyl)methylsulfoniomethyl-1,4-cyclohexanediol bromide (198 mg: yield 56%) as colorless powder.