Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(NCc2ccc(Cl)cc2)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with 4-chlorobenzylamine (2.72 g, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-(4-chloro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester (2.98 g, 10.68 mmol, 55.6%), as a light yellow oil. LC-MS (ESI) calcd for C15H18ClNO2 279.10, found 280.1 [M+H+].
Reaction SMILES: C(O)C.[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([F:17])[F:16])=[C:11](Cl)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([F:17])[F:16])=[C:11]([NH:26][CH2:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)n1ncc(Cl)c(C(F)F)c1=O
Reactant: NCc1ccncc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(C(F)F)c1=O

Procedure:
20 ml of an absolute ethanol solution of 0.71 g of 2-tert-butyl-5-chloro-4-difluoromethylpyridazin-3-(2H)-one, 0.33 g of 4-picolylamine and 0.33 g of triethylamine, was reacted for 5 hours under heating and refluxing and left to cool. Then, the mixture was extracted with ethyl acetate, then washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was subjected to column chromatography, and using an eluent (n-hexane:ethyl acetate=1:2), 0.32 g of the desired product (Compound No. 12) having a melting point of from 142° to 143° C. and 0.04 g of amorphous 2-tert-butyl-5-(4-pyridylmethylamino)-4-(4-pyridylmethyliminomethylidenyl)pyridazin-3-(2H)-one (Compound No. 2) as a by-product, were obtained.
Reaction SMILES: P(=O)(O)(O)O.[I-:6].[K+].[F:8][C:9]([F:16])([F:15])[CH:10]([CH3:14])[CH2:11][CH2:12]O>>[F:8][C:9]([F:16])([F:15])[CH:10]([CH3:14])[CH2:11][CH2:12][I:6]
Reactant: [I-]
Reactant: CC(CCO)C(F)(F)F
Agent: O=P(O)(O)O
Agent: [K+]
Product: CC(CCI)C(F)(F)F
Temperature: 0 °C

Procedure:
To a mixture of 19 g phosphoric acid (98%) and 19 g potassium iodide are added at 40° under stirring 4.75 g (33.4 mMol) of 4,4,4-trifluoro-3-methyl-butan-1-ol over a period of 10 minutes. The mixture is then heated at 120° for 16 hours, a cooling poured into ice-water and extracted with diethylether. The etheric extracts are washed with 10% sodium thiosulfate and brine acid dried over sodium sulphate. After filtration, the solvent is removed through a 15 cm Vigreux-column at atmospheric pressure, followed by fractionation giving 4,4,4-trifluoro-3-methyl-1-iodo-butane, b.p. 76°-77° at 140 mbar.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=1)(=[O:18])=[O:17])[CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])C.[Li+].[BH4-]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][CH:5]([CH2:4][OH:3])[CH:6]([C:7]([F:8])([F:9])[F:10])[C:11]([F:13])([F:12])[F:14])(=[O:17])=[O:18])=[CH:20][C:21]=1[CH3:26]
Reactant: CCOC(=O)C(NS(=O)(=O)c1ccc(F)c(C)c1)C(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)NC(CO)C(C(F)(F)F)C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of 4,4,4-trifluoro-2-(4-fluoro-3-methyl-benzenesulfonylamino)-3-trifluoromethyl-butyric acid ethyl ester (29 mg, 0.068 mmol) in anhydrous THF (3 mL) at 0° C. was added 2M LiBH4 (50 μL). The solution was allowed to warm to 25° C. After 18 h, the solution was quenched with 1N HCl and the solvent removed in vacuo. The remaining aqueous phase was transferred to a separatory funnel with distilled water (100 mL) and extracted with EtOAc (100 mL). The organic layer was removed and the aqueous phase extracted with EtOAc (100 mL×2). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), filtered and evaporated to give a white solid (21 mg). This material was purified by Gilson RP-HPLC (column YMC Combiprep 50×20 mm, gradient 10-100% CH3CN: H2O) to afford a white solid (14 mg, 54%). Mass Spectrum (−ESI): 382 [M−H]−.
Reaction SMILES: [BrH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]#[CH:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>>[Br:1][C:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=1)=[CH2:13]
Reactant: C#Cc1ccc(OC)c(OC)c1
Reactant: Br
Product: C=C(Br)c1ccc(OC)c(OC)c1
Yield: 86.7 %

Procedure:
According to the General Procedure D, HBr (33% in acetic acid, 1.11 ml, 0.50 g, 6.17 mmol) and 3,4-di-methoxyphenylacetylene (1.00 g, 6.17 mmol) are converted to give after workup and chromatography (SiO2, PE/EE 5:1, Rf=0.41) the title compound (1.30 g, 5.35 mmol, 87%) as a brown oil; C10H11BrO2 (243.10).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([O:20][C:21]1[C:30]2[C:25](=[C:26]([O:32][CH2:33][CH2:34][CH3:35])[CH:27]=[CH:28][C:29]=2[F:31])[N:24]=[CH:23][C:22]=1[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([N:24]1[C:25]2[C:30](=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH3:35])[C:21](=[O:20])[C:22]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[CH:23]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOc1ccc(F)c2c(O[Si](C)(C)C(C)(C)C)c(-c3ccc(OC)cc3)cnc12
Reactant: O=C(Cl)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(C(=O)COCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Benzyloxyacetyl chloride (1.9 ml, 3 equivalent weight) was added to a dichloromethane solution (50 ml) of 4-(tert-butyldimethylsilyloxy)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-quinolin (1.5 g, 3.4 mmol) while ice-cooling and the mixture was stirred overnight at room temperature. An aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction using ethyl acetate. The thus-obtained organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=2:1). The purified product was concentrated under reduced pressure, giving a colorless oily substance of 1-(2-benzyloxyacetyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (250 mg, yield: 15%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:15][CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:25]([C:34](OC)=[O:35])=[CH:24]2)=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.O>O1CCCC1>[CH3:7][N:8]([CH2:15][CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]([CH2:34][OH:35])=[CH:24]2)=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)c1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCOc1ccc(Cn2cc(CO)c(-c3ccccc3)c2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
Lithium aluminium hydride (305 mg) was added to a solution of methyl 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolecarboxylate (1.78 g) in tetrahydrofuran (40 ml) at 0° C., and the mixture was stirred at room temperature for 6 hours. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and [1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]methanol (1.45 g, yield: 87%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.O[NH:61][C:62](=[NH:64])[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][CH:11]2[C:12]2[O:14][N:64]=[C:62]([CH3:63])[N:61]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N2CCC[C@H]2C(=O)O)ccc(C#N)c1Cl
Reactant: CC(=N)NO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(C2CCCN2c2ccc(C#N)c(Cl)c2C)n1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(3-chloro-4-cyano-2-methylphenyl)proline (0.200 g, 0.756 mmol), TBTU (0.364 g, 1.136 mmol), diisopropylethylamine (0.458 g, 3.78 mmol) and N-hydroxybenzotriazole (0.023 g, 0.150 mmol) in DMF add N-hydroxyacetamidine (0.084 g, 1.136 mmol). Stir the solution at 21° C. for 18 h. then heat the reaction at 100° C. in a microwave for 1 h. Partition the reaction between ethyl acetate and 2N aqueous hydrochloric acid. Extract the organic phase with 2N aqueous sodium hydroxide and brine, dry over magnesium sulphate, filter and remove the solvent under reduced pressure. Purify the resulting residue by reverse phase HPLC (Princeton SPHER C-18 column, gradient of 80:20 to 5:95 [water:acetonitrile], with 0.1% acetic acid modifier)) to yield the title compound. (0.81 g, 35%) mass spectrum (m/e): 303.1 (M+Na)); 1H NMR (400 MHz, CDCl3): δ 7.35 (d, 1H), 6.99 (d, 1H), 5.11 (t, 1H), 3.88 (m, 1H), 3.16 (m, 1H), 2.56 (m, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.30-2.15 (m. 3H), 2.06 (m, 1H).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[NH:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=1>>[CH3:13][C:12]1[NH:11][C:10](=[O:14])[NH:9][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([N:19]2[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=[C:18]2[CH3:17])=[CH:3][CH:4]=1
Reactant: Cc1nc(C)c(C)[nH]1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Product: Cc1nc(C)n(-c2ccc(C(=O)c3[nH]c(=O)[nH]c3C)cc2)c1C

Procedure:
In a manner similar to Example IV react 4-(4-fluorobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one with 2,4,5-trimethyl-1H-imidazole to produce the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][C:10](=[O:15])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg+].[Br-].OS([O-])(=O)=O.[K+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][C:10](=[O:15])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)CCNC(=O)OC(C)(C)C
Reactant: C[Mg+]
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of BOC-beta-alanine (20 g, 105 mmol), 10-2 (10.3 g, 105 mmol), BOP reagent (46.5 g, 105 mmol), and N-methylmorpholine (46 mL, 420 mmol) in acetonitrile (500 mL) was stirred for 15 h. The reaction was diluted with EtOAc, washed with H2O, 10% KHSO4 (aq.), sat. NaHCO3, dried (MgSO4) and concentrated to give crude [2-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester 10-3 as a yellow oil. TLC Rf =0.42 (silica, 20% EtOAc/hexanes). To a solution of this crude amide in THF (500 mL) at 0° C. was added CH3MgBr (100 mL of 3M in ether, 300 mmol) over 30 minutes. After 2 h, 10% KHSO4 (aq.) was added, the mixture warmed to 25° C., and diluted with EtOAc. The organics were washed with sat. NaHCO3, dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 10-4 as a yellow oil.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([S:42][CH2:43][CH2:44][NH2:45])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CCO>[CH2:17]([N:13]1[C:14]2=[CH:15][N:45]([CH2:44][CH2:43][S:42][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:22])[N:11]([CH2:20][CH3:21])[C:12]1=[O:19])[CH3:18]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1c(=O)c2c(-c3ccccc3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(CC)c1=O
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-diethylpyrimidine-2,4(1H,3H)-dione (step 3) (850 mg, 2.327 mmol), 2-(tritylthio)ethanamine (commercially available, 1115 mg, 3.49 mmol) and triethylamine (0.973 mL, 6.98 mmol) were combined in EtOH (Volume: 20 mL) and the mixture heated at reflux for 20 mins. The reaction mixture was cooled to RT and evaporated under vacuum. The residue was partitioned between DCM and water and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and purification by chromatography on silica eluting with 10-50% EtOAc in iso-hexane afforded the title compound as a white solid;
Reaction SMILES: [CH2:1]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([N:5]1[CH2:6][CH2:7][O:8][C:20](=[O:22])[O:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCN(CCO)CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN1CCOC(=O)OCC1
Yield: 239.2 %

Procedure:
The procedure of Example 1 was followed using N-butyl diethanolamine (13.5 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a yellow/brown oil product (12.9 g, 82%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[C:8]([C:17]([F:20])([F:19])[F:18])=[N:9][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][C:15]=2[CH:16]=1)=[O:6])[CH3:3].[CH3:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH:33]=1)[C:30](O)=[O:31])(=[O:24])=[O:23]>>[CH2:2]([O:4][C:5]([C:7]1[C:8]([C:17]([F:19])([F:20])[F:18])=[N:9][C:10]2[CH2:11][CH2:12][N:13]([C:30](=[O:31])[C:29]3[CH:33]=[C:25]([S:22]([CH3:21])(=[O:23])=[O:24])[CH:26]=[CH:27][C:28]=3[O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:37])[F:38])[CH2:14][C:15]=2[CH:16]=1)=[O:6])[CH3:3]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCNC2
Agent: Cl
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1O[C@@H](C)C(F)(F)F)C2

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine-3-carboxylic acid ethyl ester hydrochloride (CA [741736-90-3]; WO2004069162) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): 569.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][C:3]=1[C:20](OCC)=[O:21].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:3]2[CH:4]=[N:5][C:6]3[C:7]([C:2]=2[OH:1])=[C:8]([C:16]([F:18])([F:19])[F:17])[CH:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=3)=[O:21])=[CH:28][CH:27]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)cc(C(F)(F)F)c2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)cc(C(F)(F)F)c2c1O
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.35 g of ethyl 4-hydroxy-5,7-bis(trifluoromethyl)-3-quinolinecarboxylate (FR 2537140) and 3.0 mL of 4-chlorobenzylamine is stirred 1 h at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid is completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.23 g.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:13])[CH:8]=2)[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2cc(Br)ccc2n1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2cc(Br)ccc2n1
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Crude 2,4-Dichloro-6-bromoquinazoline (18.8 g.) was dissolved in dichloromethane (500 mL) and chilled in a dry ice bath. To the solution was added morpholine (11.6 g.) and it was stirred for two hours. The organic layer was washed with saturated ammonium chloride solution (2×200 mL), dried with sodium sulfate, and evaporated. The resulting solid was washed with ether, and dried to give 2-chloro-4-morpholino-6-bromoquinazoline (15.0 g.).
Reaction SMILES: [OH:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[C@@H:3]1[OH:23].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:24][S:25]([O:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[C@@H:3]1[O:23][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:27])=[O:26]
Reactant: C[C@]12CCC(=O)C=C1[C@H](O)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C=C1[C@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
In a manner similar to that described in Example 1C, treat 6β,7α-dihydroxy-4-androstene-3,17-dione (150 mg.) in pyridine (5 ml.) with methanesulfonyl chloride (1 ml.) for two hours at room temperature. Isolate the resultant product in a manner similar to that described in Example 1C to obtain 180 mg. of 6β,7α-dimethanesulfonyloxy-4-androstene-3,17-dione which is used without further purification in the following step 31C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](O)=[O:29])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:31])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[CH3:63][O:64][NH:65][CH3:66].CN1CCOCC1.Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:43])[N:7]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28](=[O:29])[N:65]([O:64][CH3:63])[CH3:66])[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:31])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N(C)OC)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 107.2 %

Procedure:
To 10 mL of a tetrahydrofuran solution containing 600 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-carboxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 420 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 108 mg of O,N-dimethylhydroxylamine hydrochloride and 112 mg of N-methylmorpholine were added, and stirred at room temperature for 22 hours. Hydrochloric acid was added to the reaction mixture to make acidic, the organic layer was separated, washed sequentially with water, aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate], to give 0.69 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-((methoxy)(methyl)carbamoyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.Br.[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: C[C@@H]1CCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.8 %

Procedure:
A suspension of Example 1C (0.19 g, 0.55 mmol), (2R)-2-methylpyrrolidine hydrobromide (0.17 g, 1.0 mmol) and sodium carbonate (0.23 g, 2.2 mmol) in acetonitrile (0.4 mL) was heated to 50° C. with stirring for 48 hours. The reaction was cooled to ambient temperature, diluted with acetonitrile and centrifuged. The supernatant liquid was removed and the solids washed with acetonitrile. The combined liquids were concentrated under reduced pressure and the residue chromatographed by reverse phase HPLC with aqueous CF3CO2H/acetonitrile to give the titled compound (0.065 g, 34%). 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.71 (m, 4H), 7.50 (m, 2H), 6.82 (s, 1H), 3.72-3.9 (m, 2H), 3.58 (m, 1H), 3.25-3.5 (m, 4H), 2.48 (m, 1H), 2.05-2.2 (m, 2H), 1.75 (m, 1H), 1.50 (d, J=6 Hz, 3H); MS (DCI) m/z 331 (M+H)+;