Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)=[CH:5][C:4]=1C(F)(F)F)#[N:2].[NH3:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:18])([F:19])[F:20])[CH:10]([CH2:14][CH3:15])[C:11]([NH2:25])=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: N
Reactant: CCC(C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCC(C(N)=O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using 2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]butanoic acid and ammonia: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=9.0 Hz, 1H), 7.17 (d, J=2.6 Hz, 1H), 7.03 (dd, J=9.0, 2.8 Hz, 1H), 6.38 (bs, 1H), 6.27 (bs, 1H), 4.25-4.04 (m, 3H), 2.15 (m, 1H), 1.91 (m, 1H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]([CH2:13][C:14]([OH:16])=O)[CH:11]=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:17][C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:19]>>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:18]([NH:17][C:14](=[O:16])[CH2:13][N:10]2[C:9]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[N:12]=[CH:11]2)[CH3:19])=[CH:21][CH:22]=1
Reactant: O=C(O)Cn1cnc2cccc([N+](=O)[O-])c21
Reactant: C[C@H](N)c1ccc(O)cc1
Product: C[C@H](NC(=O)Cn1cnc2cccc([N+](=O)[O-])c21)c1ccc(O)cc1

Procedure:
The title compound was synthesised according to the general method of synthesis of target compounds (see below) from (7-nitro-1H-benzimidazol-1-yl)acetic acid and 4-[(1S)-1-aminoethyl]phenol. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1 H) 8.55 (d, J=8.03 Hz, 1 H) 8.40 (s, 1 H) 8.10 (d, J=8.03 Hz, 1 H) 7.98 (d, J=7.53 Hz, 1 H) 7.39 (t, J=8.03 Hz, 1 H) 7.05-7.15 (m, 2 H) 6.64-6.75 (m, 2 H) 5.19 (s, 2 H) 4.71-4.83 (m, 1 H) 1.32 (d, J=6.78 Hz, 3 H). MS (ESI) m/z: 341 [M+H]
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:27]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=[S:30])[NH:7][C:6]=2[CH:27]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCN(CCC)CC(=O)N1c2cc(Cl)c(Cl)cc2NC(=O)c2cccnc21
Solvent: c1ccncc1
Product: CCCN(CCC)CC(=O)N1c2cc(Cl)c(Cl)cc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 8,9-dichloro-6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dichloro-6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(C)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([N:14]1[CH:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Temperature: 100 °C
Yield: 62 %

Procedure:
1-Benzhydryl-5-iodo-pyrimidine-2,4-dione (0.06 g, 0.15 mmol) was suspended in a 1:1 toluene/ethanol mixture (1,6 Phenylboronic acid (0.03 g, 0.22 mmol) was added followed by 2M aqueous solution of sodium carbonate (0.082 mL, 0.16 mmol). The resulting suspension was degassed under nitrogen atmosphere for 10 min, then tetrakis(triphenylphosphine) palladium(0) (0.017 g, 0.015 mmol) was added. The reaction was heated under microwave irradiation at 100° C. for 30 min. The reaction mixture was diluted with EtOAc and water was added. The two phases were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 60:40) to afford the title compound (0.03 g, 62%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.13 (s, 1H), 7.20-7.24 (m, 5H), 7.25 (s, 1H), 7.32-7.35 (m, 5H), 7.37-7.44 (m, 5H), 8.19 (br s, 1H). MS (ESI) to/z: 355 [M-H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:16]([O:24]C)(=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>C(O)(C)(C)C>[CH3:22][O:21][C:19](=[O:20])[C:18](=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([F:7])=[CH:9][CH:10]=1)[CH2:17][C:16]([OH:24])=[O:23]
Reactant: COC(=O)CCC(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Yield: 66.5 %

Procedure:
To a refluxing mixture of potassium tert-butoxide (27 g, 242 mmol) and tert-butanol (150 mL) was added a solution of 4-fluoro-benzaldehyde (20 g, 161 mmol) and dimethyl succinate (28 g, 193.2 mmol) in tert-butanol (100 mL) dropwise. After being stirred at reflux for 3 hours, the mixture was concentrated in vacuo to remove tert-butanol. The residue was dissolved in 1 N hydrochloric acid (180 mL). The resulting aqueous solution was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to afford 2-(4-fluoro-benzylidene)-succinic acid 1-methyl ester (25.5 g, 66%) as a light yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.84 (s, 1H), 7.41-7.46 (m, 2H), 7.13-7.20 (m, 2H), 3.81 (s, 3H), 3.49 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:41][CH2:40][CH2:39][N:38]([CH3:42])[CH3:37])=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: CN(C)CCN
Agent: CCOP(=O)(C#N)OCC
Product: CN(C)CCNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(5chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent Mass: 577.31 (M+H).
Reaction SMILES: [N+](CP(=O)([O:8][CH2:9][CH3:10])OCC)#[C-].C([Li])CCC.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27]C(=O)[CH2:25]2)=[CH:20][CH:19]=1.Cl>CCOCC>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[CH2:27][C@H:10]([CH:9]=[O:8])[CH2:25]2)=[CH:20][CH:19]=1
Reactant: O=C1CC(c2ccc(Br)cc2)C1
Reactant: [C-]#[N+]CP(=O)(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C[C@H]1C[C@H](c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of diethyl isocyanomethylphosphonate (0.86 mL, 5.3 mmol) in anhydrous ether (45 mL) at −78° C. under nitrogen was added n-butyl lithium (2.13 mL, 2.5 M in hexane) and the resulting mixture was stirred at −78° C. for 1 hr. Then, 3-(4-bromo-phenyl)-cyclobutanone (1 g, 4.4 mmol) in anhydrous ether (15 mL) was added dropwise over 30 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred 16 hours. Concentrated hydrochloric acid (9.5 mL) was added dropwise and the reaction mixture was stirred at room temperature for 5 hrs. The mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel eluting with 2-3% ethyl acetate in hexanes to provide 3-(4-bromo-phenyl)-trans-cyclobutanecarbaldehyde (281 mg, 27%) as the faster eluting isomer (A1) and 3-(4-bromo-phenyl)-cis-cyclobutanecarbaldehyde (508 mg, 48%) as the slower eluting isomer (A2). A1: 1H NMR (300 MHz, CDCl3) δ 2.37 (m, 2 H), 2.72 (m, 2 H), 3.16 (m, 1 H), 3.53 (p, J=6 Hz, 1 H), 7.09 (d, J=9 Hz, 2 H), 7.44 (d, J=9Hz, 2 H), 9.95 (s, 1 H),; (DCl/NH3) m/z 239 (M+H)+; A2: 1 H NMR (300 MHz, CDCl3) δ 2.35 (m, 2 H), 2.55 (m, 2 H), 3.21 (m, 1 H), 3.52 (p, J=6 Hz, 1 H), 7.07 (d, J=9 Hz, 2 H), 7.42 (d, J=9 Hz, 2 H), 9.73 (s, 1 H); (DCl/NH3) m/z 239 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][O:21][CH3:22]>>[C:3]([OH:19])(=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][O:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Agent: COC
Product: CCCCCCCCCCCCCCCC(=O)O
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Palmitic acid methyl ester (2.00 g; 7.40 mmol) was combined with poly(ethylene glycol) (PEG-12) monomethyl ether 550 (4.41 g; 7.40 mmol; 1.0 equiv) having an average molecular weight of 596 (available from Sigma-Aldrich Chemical Company) in a 40-milliliter vial equipped with a magnetic stir bar. Immobilized Candida antarctica lipase B immobilized on a porous fluoropolymer support as described in US published Patent Application 2012/0040395 was added to the flask in an amount of 0.13 grams, (2 wt % based on the total weight of starting materials). The mixture was stirred and heated to 65° C. and purged with a subsurface stream of nitrogen at a rate of 100 mL/min. After 24 hours a final sample was removed and analyzed by GC to determine conversion of methyl palmitate to palmitic acid methyl ester ethoxylate. Conversion was as follows: after 3 hours, 64.8%; after 6 hours, 80.8%, after 12 hours, 92.1%; and after 23 hours, 96.4%.
Reaction SMILES: [Br:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([S:8][C:13]([CH3:15])([CH3:14])[C:12]([O:11][CH2:9][CH3:10])=[O:17])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1ncccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1ncccc1Br
Temperature: 70 °C
Yield: 89.1 %

Procedure:
A mixture of 3-bromopyridine-2-thiol (189 mg, 1 mmol), ethyl-2-bromoisobutyrate (390 mg, 2 mmol) and sodium carbonate (159 mg, 1.5 mmol) in DMF (2 mL) was heated to 70° C. for 1 hour. The reaction mixture was neutralized with HCl aq. 1M and extracted with ethyl acetate. The organic layer was dried over Mg2SO4, concentrated and purified by chromatography to yield ethyl 2-(3-bromopyridin-2-ylthio)-2-methylpropanoate (0.271 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O:21]C)=O)[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:24][CH3:23])=[O:21])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Solvent: O
Product: CNC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 120 °C

Procedure:
A mixture of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.45 g, 1.5 mmol) and 20 mL of methylamine (40% aqueous solution) was heated at 120° C. in a sealed tube for 16 hours. After cooling, water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to afford 0.4 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide as a white solid, mp: 88-89° C. Anal. Calc'd for C16H13FN4O+0.4 H2O: C, 63.32; H, 4.58; N, 18.46. Found C, 63.10; H, 4.62; N, 18.35.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]Br)=[CH:24][C:23]=1[N+:32]([O-:34])=[O:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:23]([N+:32]([O-:34])=[O:33])[CH:24]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(OCCN2CCC(Cc3ccccc3)CC2)ccc1OCc1ccccc1
Yield: 77.1 %

Procedure:
From a mixture of 4-benzylpiperidine (2.68 9, 15.1 mmol), 2-(4-benzyloxy-3-nitrophenoxy)ethyl bromide (2.65 g, 7.52 mmol) and KI (110 mg) in toluene (25 mL) was obtained 2.59 g (77%) of 4-benzyl-1-(2-(4-benzyloxy-3-nitrophenoxy)ethyl)piperidine as an orange-yellow oil. 1H NMR (CDCl3): 1.30-1.42 (m, 2H), 1.50-1.60 (m, 1H), 1.64-1.68 (m, 2H), 2.02-2.10 (m, 2H), 2.547 (d, 2H, J=7), 2.777 (t, 2H, T=6), 2.95-3.00 (m, 2H), 4.085 (t, 2H, J=6), 5.181 (s, 2H), 7.02-7.46 (m, 8H).
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:34][C:35]([O:37][CH3:38])=[O:36])[CH2:20][C@@H:21]3[O:29][C:30]([O:32][CH3:33])=[O:31])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1>CC(C)=O.S(=O)(=O)(O)O>[CH3:33][O:32][C:30]([O:29][C@@H:21]1[C@@:22]2([CH3:23])[C:17](=[CH:16][CH:15]=[C:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[CH:8]([CH:5]=[O:4])[CH3:9])[CH2:18][C@@H:19]([O:34][C:35]([O:37][CH3:38])=[O:36])[CH2:20]1)=[O:31]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C
Yield: 65.3 %

Procedure:
In 5 ml of acetone was dissolved 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene, followed by addition of one drop of concentrated sulfuric acid, and the mixture was refluxed in an atmosphere of argon gas for 3 hours. The reaction mixture was poured in ice-water and extracted with ether. The extracts were pooled and washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, followed by concentration under reduced pressure. Finally the concentrate was purified by recrystallization from ether. The procedure yielded 55 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:17]1[CH:16]=[C:15]([CH:7]([C:5]2[S:6][C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:3][CH:4]=2)[C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:20]=[CH:19][CH:18]=1
Reactant: C1COCCN1
Reactant: COC(=O)C(C)(C)C(c1cccc(F)c1)c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)C(c1cccc(F)c1)c1ccc(N2CCOCC2)s1
Temperature: 80 °C
Yield: 32.2 %

Procedure:
A mixture of methyl 3-(5-bromothiophen-2-yl)-3-(3-fluorophenyl)-2,2-dimethyl-propanoate, product of Preparation 1, Step 2, (367 mg, 0.988 mmol), morpholine (0.572 mL), palladium acetate (44 mg, 0.20 mmol), 2-(di-tert-butylphosphino)-biphenyl (118 mg, 0.40 mmol), and sodium tert-butoxide (228 mg, 2.37 mmol) in toluene (5 ml) was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, the solid was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography using 20% ethyl acetate in hexanes to give methyl 3-(3-fluorophenyl)-2,2-dimethyl-3-(5-morpholinothiophen-2-yl)propanoate as an oil (120 mg, 32.2%). LC/MS (m/z) 378.33 [(M+H)+]; HPLC Rt: 3.548 min.
Reaction SMILES: Cl.O1CCCCC1[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:32][C:30]([F:31])([F:33])[O:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:9]([OH:8])[C:10]=3[CH2:11][CH2:12][CH2:13]2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)Oc1ccc(OCCCN2CCCc3c(OC4CCCCO4)cccc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc2c1CCCN2CCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A 1 N hydrochloric acid aqueous solution (10 ml) was added to an ethanol solution (15 ml) of 5-(tetrahydropyran-2-yloxy)-1-[3-(4-trifluoromethoxyphenoxy)propyl]-1,2,3,4-tetrahydroquinoline (1.71 g) and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added thereto, and the mixture was concentrated under reduced pressure. The residue was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to afford the title compound as a colorless oil (0.62 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]([CH:19]3[CH2:21][CH2:20]3)[O:10][C:11]=2[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=1)=O.COCCO[AlH2-]OCCOC.[Na+]>O1CCCC1.CC(OC)(C)C>[CH:19]1([CH:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:5]=3[CH2:3][OH:2])[O:10]2)[CH2:20][CH2:21]1
Reactant: COC(=O)c1cc(OC)c(OC)c2c1C=CC(C1CC1)O2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COc1cc(CO)c2c(c1OC)OC(C1CC1)C=C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
Methyl ester 2 (2 g, 6.2 mmol) was dissolved in 30 ml tetrahydrofurane and 2.7 ml of a 3.5-M solution of Red-Al (9.4 mmol) was added. The mixture was stirred at 40° C. for 3 hours. The solution was diluted with 100 ml of TBME and slowly quenched by addition of 50 ml of a 30% potassium-tartrate solution. The layers were separated and the organic solution was washed with brine (2 times 30 ml), dried over magnesium sulfate and concentrated. The pure alcohol 4 (1.34 g, 5.1 mmol) was obtained as a white-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1-c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1-c1ccccc1

Procedure:
A solution of product from step C, (9.5 g; 42 mmol), N-bromosuccinimide (NBS) (8.22 g; 46.2 mmol), 2,2′-azobis(2′-methylpropionitrile) (25 mg; 0.15 mmol) and benzoylperoxide (25 mg; 0.1 mmol) in CCl4 (100 ml) was heated at reflux for 5 hours. The solid was filtered and the filtrate evaporated to give methyl 4-bromomethyl-2-phenylbenzoate as an oil (9.43 g; 74%) which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([CH3:42])([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH2:33][CH3:34])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:33]([N:17]1[CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:42])([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:4]([OH:43])=[O:3])=[CH:8][CH:9]=2)[CH2:20][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=2)[C:18]1=[O:32])[CH3:34]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2CC)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution of 3-(4-{2-[3-Ethyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.31 g, 0.518 mmol) and 5N NaOH (1 mL) in ethanol (9 mL) is refluxed for 1 hour, cooled to ambient temperature, and concentrated. The residue is diluted with CH2Cl2, washed, dried, and concentrated in vacuo to provide the title compound (0.256 g, 87%). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 2H, J=7.6 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.21-7.17 (m, 4H), 6.97 (t, 1H, J=7.6 Hz), 6.88 (d, 2H, J=7.6 Hz), 6.72 (d, 2H, J=8.4 Hz), 4.42, 4.38 (ABq, 2H, J=15.1 Hz), 3.94 (t, 2H, J=5.9 Hz), 3.87-3.81 (m, 1H), 3.62-3.53 (m, 1H), 3.36 (t, 1H, J=8.4 Hz), 3.31, 3.08 (ABq, 2H, J=8.4 Hz), 3.15-3.08 (m, 1H), 3.00 (t, 1H, J=8.4 Hz), 2.23-2.19 (m, 1H), 1.89-1.82 (m, 1H), 1.37 (s, 3H), 1.13 (t, 3H, J=6.7 Hz). MS [EI+] 571 (M+H)+, [EI−] 569 (M−H)+.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[CH:6]=1>CN(C=O)C>[F:12][C:7]1[CH:6]=[C:5]([C:2]#[N:3])[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: N#C[Cu]
Reactant: Cc1ccc(Br)cc1F
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1F
Temperature: 150 °C
Yield: 58 %

Procedure:
Copper(I) cyanide (Aldrich, 3.6 g, 40 mmol) was added to a solution of 4-bromo-2-fluorotoluene (Aldrich, 5 g, 27 mmol) in DMF (60 mL). The reaction mixture was heated at 150° C. for 11 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc (500 mL each). The organic layer was dried (MgSO4), and solvent was removed under vacuum to give the title compound (2.08, 58%). 1HNMR (CDCl3) δ2.36 (s, 3H), 7.30 (m, 3H), 7.35 (d, 1H, J=8.1 Hz).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1.[CH3:18]O>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:18])=[O:11])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (31.5 ml; 0.432 mol) was slowly added dropwise at 0° C. to a solution of 4-fluoro-2-nitrobenzoic acid (16.0 g; 86.4 mmol) in methanol (240 ml). After warming to RT, stirring overnight and boiling under reflux for 4 h, the reaction solution was concentrated in vacuo and partitioned between ethyl acetate and potassium hydrogencarbonate solution. Drying and concentration of the organic phase afforded a yellow oil.