Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(CC)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(NCCCN(C)C)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 8.7 g. (0.03 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, (Example 30) 3.06 g. (0.03 mole) of 3-dimethylaminopropylamine and 3.18 g. of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 150 ml. of water and was extracted with 150 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and the ether was evaporated. The residue was passed through a neutral aluminum oxide column using ethyl acetate as the eluent. The ethyl acetate was evaporated and the residue was dissolved in anhydrous diethyl ether and the solution was acidified with an etheral hydrochloric acid solution. The precipitate which formed was collected and was dried to give 1.9 g. of product as the hydrochloride, monohydrate, m.p. 75° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14](O)=[O:15])([O-:3])=[O:2].O.CCCCCC>O1CCCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
22.6 g (100 mmol) 2,4-dinitrophenylacetic acid is dissolved in 150 ml tetrahydrofuran and added dropwise in a the course of 2 hours to 300 ml (300 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydrofuran. After 3 hours at 25° C., 200 ml water is carefully added. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 400 g silica gel using toluene:ethyl acetate 1:1 as eluant and crystallization form ethylacetate:hexane mixture to yield 20.7 g (98%) of 2-(2,4-dinitrophenyl)ethanol as yellowish crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[O:10][CH2:9][C:8](=O)[CH2:7]2.[CH2:15]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1C=CC=CC=1.[Pd].C(O)C>[CH2:15]([N:18]([CH2:19][CH2:20][CH3:21])[CH:8]1[CH2:7][C:6]2[C:11](=[CH:2][CH:3]=[CH:4][C:5]=2[O:13][CH3:14])[O:10][CH2:9]1)[CH2:16][CH3:17]
Reactant: COc1ccc(Br)c2c1CC(=O)CO2
Reactant: CCCNCCC
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: CCCN(CCC)C1COc2cccc(OC)c2C1
Yield: 76.7 %

Procedure:
To a solution of 8-bromo-5-methoxy-3-chromanone (125 mg, 0.49 mmol) in benzene (20 ml) was added di-n-propylamine (0.5 ml, 3.7 mmol) and p-toluenesulfonic acid monohydrate (10 mg, 0.08 mmol). The solution was refluxed for 5 hours with a Dean-Stark apparatus under N2 -atmosphere. The reaction mixture was poured into a Parr-flask, absolute ethanol was added (50 ml) and pH was adjusted to 11 with 2M-NaOH-solution. The product was hydrogenated overnight with Pd/C as catalyst. The catalysst was filtered off and the solvent was evaporated. The residual oil was dissolved in CH2Cl2 and washed with 5% aqueous Na2CO3. The phases were separated and the organic layer was dried (Na2CO3) yielding 99 mg (77%) of the product as an oil with physical data identical with authentic material synthesized by alternative methods.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:36])=[C:14]([C:16]2[CH:17]=[C:18]3[C:24]([C:25]([O:27]C)=[O:26])=[C:23]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[O:22][C:19]3=[N:20][CH:21]=2)[CH:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.C1COCC1.CCOC(C)=O>[C:3]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:36])=[C:14]([C:16]2[CH:17]=[C:18]3[C:24]([C:25]([OH:27])=[O:26])=[C:23]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[O:22][C:19]3=[N:20][CH:21]=2)[CH:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)OC(C)(C)C)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1-c1cnc2oc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Reaction time: 4 h
Yield: 100 %

Procedure:
NaOH (1.4 mL, 1.37 mmol) was added to a stirring solution of methyl 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate (211 mg, 0.457 mmol) in MeOH (2.3 mL) and THF (2.3 mL) at 60° C. It was allowed to stir for 4 hours. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid (205 mg, 0.457 mmol, quant.) consistent by LCMS crude which was used directly in the next step. LC-MS retention time: 1.88 min; m/z (MH+): 448. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:26])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:26])[CH2:15][N:16]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COC(=O)CNCc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(O)cc1

Procedure:
To a solution of 8.7 g (45.2 mmol) of 4-hydroxybenzenesulfonyl chloride in 80 ml of CH2Cl2, a solution of 6.75 g (32.3 mmol) of (4-methoxy-benzylamino)-acetic acid methyl ester in 20 ml of CH2Cl2 and 12 ml (79.2 mmol) of triethylamine were added dropwise at 0° C. The resulting mixture is stirred for 4 h at r.t., neutralized with cold 1 N aqueous HCl and extracted with CH2Cl2. The combined extracts are washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:CH2Cl2=50:1˜5:1) to give [(4-hydroxy-benzenesulfonyl)-(4-methoxy-benzyl)-amino]-acetic acid methyl ester; NMR (CDCl3): 3.57 (s, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.40 (s, 2H), 5.59 (s, 1H), 6.84 (d, 2H, J=8.6 Hz), 6.93 (d, 2H, J=10.64 Hz), 7.15 (d, 2H, J=8.6 Hz), 7.82 (d, 2H, J=10.64 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:21]=1.C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:29]1[CH2:30][CH2:31][N:26]([C:22]2[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[CH:24][N:23]=2)[CH2:27][CH2:28]1)=[O:7])#[N:2]
Reactant: N#Cc1ccccc1C(=O)O
Reactant: COc1ccnc(N2CCNCC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccnc(N2CCN(C(=O)c3ccccc3C#N)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
To a suspension of 2.0 g (14 mmol) of 2-cyanobenzoic acid in 100 mL of CH2Cl2 are added 1.5 mL (17.5 mmol) of oxalyl chloride and a catalytic amount of pyridine. The suspension is left stirred at room temperature for 3 hours. The solvent is evaporated at reduced pressure, giving a crude which is suspended in 100 mL of CH2Cl2 and which is slowly added on a solution of 2.45 g (12.6 mmol) of 4-methoxy-2-(1-piperazinyl)pyrimidine and 4 mL (28 mmol) of triethylamine in 50 mL of CH2Cl2 cooled to 0° C. in an ice bath. The solution is kept at 0° C. for one hour and is allowed to reach room temperature. The reaction mixture is washed with H2O, dried with Na2SO4 and the solvent eliminated at reduced pressure. The resulting crude is purified by chromatography on silica gel, using ethyl acetate as eluent, providing 2.06 g (6.4 mmol) of 2-[4-(2-cyanobenzoyl)-1-piperazinyl]-4-methoxipyrimidine with m.p.=166-168° C.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.Cl.CC[Cl:23]>CC(C)=O.C(OCC)C>[ClH:23].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:13][CH:14]=1
Reactant: COc1ccc([C@H](CO)NC(=S)NC(C)(C)C)cc1
Reactant: CCCl
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2CSC(N)=N2)cc1

Procedure:
The process is performed under the conditions of Example 1, starting with 2.5 g of N-(tert-butyl)-N′-[(1R)-1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea in 25 cm3 of aqueous 6N hydrochloric acid for 3 hours at a temperature in the region of 100° C. The reaction mass is evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. 15 cm3 of aqueous 1N sodium hydroxide and 5 cm3 of water are added to the residue obtained. The mixture is extracted with 20 cm3 of ethyl acetate and the organic phase is then concentrated as above. The product obtained is purified by chromatography, under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-63μ; mass of silica 80 g), eluting with an ethyl acetate/methanol mixture (80/20 by volume), and collecting about 10 cm3 fractions. Fractions 10 to 16 are combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.23 g of a lacquer is obtained, the hydrochloride of which is prepared in the following way: the product is dissolved in 2.5 cm3 of acetone and 1 cm3 of diethyl ether, followed by addition thereto of 2 cm3 of 4.5N hydrochloric ether. A crystalline product precipitates. It is filtered off, washed 3 times with acetone and then dried at a temperature in the region of 40° C. under reduced pressure (10 Pa). 0.09 g of (−)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of a white solid melting at 236° C. (αD20=−79.6±1.3 at a concentration of 0.5% in methanol).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([C@@H:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:5].C(OC(C)C)(=O)C.COC1C=CC(CN2C(C(O)=O)CSC2=O)=CC=1.CN1CCOCC1.C(Cl)(=O)C(C)(C)C.CONC>CCCCCCC>[CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:5]
Reactant: COc1ccc(CN2C(=O)SC[C@H]2C(=O)N(C)OC)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: CNOC
Agent: COc1ccc(CN2C(=O)SCC2C(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCC
Product: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
Preparation of (R)-(−)-3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (A compound of Formula V): A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with an iso-propyl acetate solution of 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid (310.0 g, 1.16 mol, approximately 3 L). The vessel was purged with nitrogen and cooled to 0° C. 4-Methyl-morpholine (130.0 g, 1.29 mol) was added while maintaining an internal reaction temperature below 5° C. Pivaloyl chloride (150.0 g, 1.24 mol) was added dropwise such that the internal reaction temperature was maintained below 5° C. The reaction was stirred at 0° C. for 45 minutes. N-Methoxy-methanamine (78.0 g, 1.28 mol) was added while maintaining an internal reaction temperature below 5° C. The reaction was monitored by HPLC and was considered complete when the ratio of the product to starting material was 4:1 (approximately 30 minutes after amine addition). The mixture was then washed with a 2.4 L portion of 0.1 M HCl, followed by 2.4 L of saturated NaHCO3. The organic phase was separated and concentrated to a final volume of 1.0 L by distillation. After a precipitate began to form, a 250 mL portion of n-heptane was added. The mixture was stirred vigorously. The solid was filtered and dried in a vacuum oven at 40° C. Approximately 250 g of 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide was obtained (70% yield). 1H NMR (300 MHz, DMSO) δ 7.15 (d, 8.9 Hz, 2H), 6.86 (d, 8.9 Hz, 2H), 4.49 (AB, JAB=14.4 Hz, ΔνAB=387.9 Hz, 2H), 4.40 (dd, J=8.8, 5.2 Hz, 1H), 3.79 (s, 3H), 3.46 (dd, J=11.0, 8.5 Hz, 1H), 3.38 (s, 3H), 3.21 (s, 3H), 3.15 (dd, J=11.0, 5.5 Hz, 1H). 13C NMR (75 MHz, DMSO) δ 28.4, 32.9, 47.2, 55.8, 57.9, 61.9, 114.7, 128.5, 130.3, 159.5, 169.4, 172.3; [α]26.5D-93.5° (c=1.0 EtOH). The enantiomeric purity of (R)-(−)-3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide can be measure using the described HPLC method.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([CH3:13])=[CH:4][N:3]=1.Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C=O)C.O.N1C=CC=CC=1>[CH3:13][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]2[N:3]([CH:4]=1)[CH2:15][CH2:16][S:17](=[O:19])(=[O:18])[N:1]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCOC(=O)c1cc(C)cnc1N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C1=CC(C)=CN2CCS(=O)(=O)N=C12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-amino-5-methylpyridine-3-carboxylate (368 mg) in DMF (20 mL) were added pyridine (0.66 mL) and 2-chloroethanesulfonyl chloride (0.32 mL), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added water (50 mL) and sodium carbonate (1 g), sodium chloride was saturated and the mixture was extracted 3 times with ethyl acetate. The extracts were collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (111 mg) as a brown solid.
Reaction SMILES: [N+:1](=[CH:3][CH2:4][O:5][C:6]([CH2:8][C:9]1(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])=[N-:2].O(C(C)C)C(C)C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>N1C=CC=CC=1>[N+:1](=[CH:3][CH2:4][O:5][C:6]([CH2:8][C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=1)=[O:7])=[N-:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC(=O)OCC=[N+]=[N-])CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(CC(=O)OCC=[N+]=[N-])CC1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
78.0 ml of dry pyridine are added to a solution of 15.12 g of tert-butyl 4-(diazoethoxycarbonylmethyl)-4-hydroxypiperidine-1-carboxylate into 250 ml of iPr2O. The mixture is cooled to −10° C. and 8.86 ml of POCl3 are added slowly with vigorous stirring. The mixture is then left to return to ambient temperature for 12 hours with stirring. The reaction mixture is decomposed with 500 ml of a 0.1 M NaOH solution, and is then extracted 3 times with EtOAc. The organic phase is washed with a saturated NaCl solution and dried over MgSO4. The hydrated salt is removed by filtration and the dry filtrate is concentrated under reduced pressure to 1/10 of its initial volume. LC/MS: RT=4.57; [M+1]+=296.31 The product is used as it is for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:29])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:29][CH3:30])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:18][CH2:19]2)=[O:16])=[N:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Nc1ncc(C(O)c2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid [5-[(2-chloro-phenyl)-hydroxy-methyl]-thiazol-2-yl]-amide (25 mg, 0.058 mmol) was placed in 1 mL of toluene with p-toluenesulfonic acid (14 mg, 0.073 mmol). Methanol (3.0 L, 0.075 mmol) was added and the solution was subjected to microwave irradiation for 5 minutes at 150° C. The mixture was then evaporated to dryness and purified by reverse-phase preparative liquid chromatography to yield the pure product. (6.0 mg, 0.013 mol, 22%). ESI-MS m/z calc. 515.1. found; 443.3 (M+1)+ Retention time 3.72 minutes. 1H NMR (400 MHz, CD3CN) δ 1.23-1.30 (m, 2H), 1.56-1.67 (m, 2H), 3.38 (s, 3H), 5.88 (s, 1H), 5.99 (s, 2H), 6.84 (d, J=6.2 Hz, 1H), 6.92-6.98 (m, 2H), 7.26 (s, 1H), 7.33-7.38 (m, 1H), 7.41-7.48 (m, 2H), 7.62-7.71 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].[Si:32]([O:39][C@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:41]1[CH2:52]O)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Si:32]([O:39][C@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:41]1[CH2:52][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:5]2[C:6]3[C:11](=[C:10]([NH:12][C:13]([C:15]4[N:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]5=[N:17][CH:16]=4)=[O:14])[CH:9]=[CH:8][CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)[N:26]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CO
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(OC[C@H]3[C@@H](O[Si](C)(C)C(C)(C)C)CCN3C(=O)OC(C)(C)C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 16 h

Procedure:
To a suspension of N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (26 mg, 0.0630 mmol; prepared as in Example 17, Step A) in THF (5 mL) was added (2S,3S)-tert-butyl 3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (62.7 mg, 0.189 mmol), triphenylphosphine (54.6 mg, 0.208 mmol) and diethyl azodicarboxylate (81.9 μL, 0.208 mmol). The suspension became a clear solution, which was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and silica gel chromatography (DCM/MeOH 10:1) provided the product mixed with triphenyl phosphine oxide (65.6 mg).
Reaction SMILES: C1O[C:4]2([CH2:21][C@H:20]([CH3:22])[C@@:19]3([CH2:23][OH:24])[C:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][CH2:12][C@@H:13]3[OH:25])=[CH:5]2)SC1>[Ni].CO>[CH3:22][C@@H:20]1[C@@:19]2([CH2:23][OH:24])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:25])=[CH:5][CH2:4][CH2:21]1
Reactant: C[C@H]1CC2(C=C3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31CO)OCCS2
Agent: [Ni]
Solvent: CO
Product: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO

Procedure:
Raney nickel is added to a solution of the above 17β,19-dihydroxy-1α-methyl-4-androsten-3-one 3-ethylenethioketal in methanol and the resulting suspension is refluxed for about 4 hours with rapid stirring. The suspension is cooled, filtered and the solvent evaporated. The residue is chromatographed on silica gel and eluted with methylenechloride. Recrystallization from acetone-hexane yields 1α-methyl-4-androstene-17β,19-diol.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C1(C)C=CC=CC=1.CO>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC

Procedure:
The results of the flux and retention tests of 1.0%, by weight, solutions of n-docosane in n-hexane and in toluene and of a 1.0%, by weight, solution of PEG 300 in methanol, evaluated at room temperature and a pressure of 40 bars, are mentioned in Table C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[OH:19])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1CCCC[CH2:21]1.C(OC(OCC)OCC)C.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:10])[C:11]3[C:12](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[O:19][CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(C(=O)Cc2cccc(F)c2)c(O)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(OCC)OCC
Product: COc1ccc2c(=O)c(-c3cccc(F)c3)coc2c1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
2-(3-Fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone (1.76 g) was dissolved in pyridine (88 ml). Piperidine (8.8 ml) and triethylorthoformate (88 ml) were added and the mixture was stirred at 120° C. for 3.5 hours. After pouring the mixture into water and acidification with conc. HCl the crude product was filtered. Purification by column chromatography using heptane-ethyl acetate (7:3) as an eluant afforded 3-(3-fluorophenyl)-7-methoxychromen-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.57 (s, 1H), 8.06 (d, 1H, J 8.9 Hz), 7.45-7.50 (m, 3H), 7.21-7.25 (m, 1H), 7.20 (d, 1H, J 2.4 Hz), 7.12 (dd, 1H, J 8.9, 2.4 Hz), 3.92 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.OS(O)(=O)=O>CO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH2:18][C:2]([CH2:6][CH3:7])([OH:1])[C:3]([OH:5])=[O:4])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CCC(=O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(O)(CC(=O)c1cccc(Cl)c1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A RBF was charged with 2-oxobutanoic acid (2.50 g, 24.5 mmol) and 3.2 mL of water and the mixture was cooled to 0° C. The acid was neutralized by slow addition of 20% aqueous KOH. 3′-chloroacetophenone (3.79 g, 24.5 mmol) was added, followed by a 1.3 M solution of KOH (2.20 g, 39.2 mmol) in MeOH. The reaction mixture was stirred at 0° C. for 48 h. The mixture was brought to pH 2 by dropwise addition of conc. H2SO4. The MeOH was removed in vacuo, and 25 mL of water was added. The heterogeneous mixture was filtered through Celite, and the filter cake was washed with water and CH2Cl2. The layers of the filtrate were separated, and the aqueous portion was extracted with additional CH2Cl2. The combined organics were dried with MgSO4, filtered and concentrated to a volume of 25 mL. Hexane was added until the mixture became cloudy, and upon standing a white crystalline solid formed. The mother liquor was decanted and the solids were washed with hexane and dried to provide 4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid as a white crystalline solid. MS m/z=279 [M+Na]+. Calc'd for C12H13ClO4: 256.69.