Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[S:10](=[O:20])(=[O:19])[N:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.O>[CH3:18][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:10]([C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:20])=[O:19]
Reactant: COC(=O)c1cccnc1S(=O)(=O)N(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccccc1)S(=O)(=O)c1ncccc1CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
A mixture of 2-(methylphenylsulfamoyl)nicotinic acid methyl ester (1.5 g) and tetrahydrofuran (50 mL) at −78° C. was treated with a 1.0 M solution of lithium aluminium hydride in tetrahydrofuran (10 mL), and the resulting mixture was stirred at −78° C. for 1 hour and then at room temperature for 2 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined organic extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1:0 to 19:1 by volume) to afford the title compound (0.25 g).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH:9]=[CH:8]2)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:23])[C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[N:14][CH:13]=2)[CH:8]=[CH:9][C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(ccc(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(ccc(=O)n2Cc2ccccc2)c1O
Yield: 69.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.13 mmol), β-alanine (920 mg, 10.3 mmol) and NaOMe solution (15 mL, 7.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 33 mg of the title compound as an off-white solid. MS: (+) m/z 368.24 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@:10]1([N:30]=[N+:31]=[N-:32])[C@@H:15](OS(C(F)(F)F)(=O)=O)[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6].C(OCC)C>CN(C)C=O>[CH2:5]([O:7][C:8]([C@:10]1([N:30]=[N+:31]=[N-:32])[C@H:15]([N:1]=[N+:2]=[N-:3])[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N=[N+]=[N-])[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
56 mg of sodium azide was added to 250 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 5 mL of N,N-dimethylformamide, and the mixture was stirred for 30 minutes at room temperature. After 100 mL of diethyl ether was added to the reaction solution, this ether solution was washed four times with water and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=10:1), thereby yielding 175 mg of (1R,2R,3R,5R,6R)-2,3-diazido-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCOC(/N=N/C(OCC)=O)=O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCCCO)cc1
Reaction time: 16 h
Yield: 68 %

Procedure:
To a solution of methyl p-hydroxybenzoate (3.38 g), 1,5-pentanediol (2.30 g) and triphenylphosphine (5.96 g) in tetrahydrofuran (100 mL), diethylazodicarboxylate (2.2N toluene solution, 10 mL) was slowly added under ice cooling. The reaction mixture was stirred under ice cooling for 16 hours. The reaction mixture was concentrated and the residue was washed with n-hexane-ethyl acetate solution (n-hexane:ethyl acetate=1:1). The reaction mixture was concentrated and then purified by silica gel chromatography (n-hexane:ethyl acetate=64:36→45:55) to obtain the title compound (3.58 g) having the following physical properties.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]=[C:13]2[C:16]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)C.[OH-].[K+]>C(O)C.O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:16]2([C:13]3[C:14]4[C:9](=[CH:8][CH:7]=[C:6]([NH2:5])[CH:15]=4)[CH2:10][CH2:11][N:12]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)Nc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Yield: 100 %

Procedure:
{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yl}-carbamic acid ethyl ester (400 mg, 1.04 mmol) in a solution of potassium hydroxid in ethanol (20 ml, 10%) are stirred for 5 h under reflux. The solvent was reduced, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution and dried with sodium sulphate to give the final product (0.32 mg, 1.04 mmol, 99%) as an orange solid that was used without further purification.
Reaction SMILES: CC1[N:3](CC(C)C)C2C3C=CC(OCCC4CCNCC4)=CC=3N=C(N)C=2N=1.[CH3:29][C:30]1[N:31]([CH2:61][CH:62]([CH3:64])[CH3:63])[C:32]2[C:41]3[CH:40]=[CH:39][C:38]([O:42][CH2:43][CH2:44][CH:45]4[CH2:50][CH2:49][N:48]([C:51]([N:53]5[CH2:58][CH2:57][O:56][CH2:55][CH2:54]5)=[O:52])[CH2:47][CH2:46]4)=[CH:37][C:36]=3[N:35]=[C:34](N)[C:33]=2[N:60]=1>>[CH3:29][C:30]1([NH2:3])[NH:60][C:33]2[CH:34]=[N:35][C:36]3[CH:37]=[C:38]([O:42][CH2:43][CH2:44][CH:45]4[CH2:50][CH2:49][N:48]([C:51]([N:53]5[CH2:58][CH2:57][O:56][CH2:55][CH2:54]5)=[O:52])[CH2:47][CH2:46]4)[CH:39]=[CH:40][C:41]=3[C:32]=2[N:31]1[CH2:61][CH:62]([CH3:64])[CH3:63]
Reactant: Cc1nc2c(N)nc3cc(OCCC4CCNCC4)ccc3c2n1CC(C)C
Reactant: Cc1nc2c(N)nc3cc(OCCC4CCN(C(=O)N5CCOCC5)CC4)ccc3c2n1CC(C)C
Product: CC(C)CN1c2c(cnc3cc(OCCC4CCN(C(=O)N5CCOCC5)CC4)ccc23)NC1(C)N

Procedure:
A modification of the method described in Example 19 was used to convert 2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine to 0.195 g of 2-methyl-1-(2-methylpropyl)-7-{2-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]ethoxy}-1H-imidazo[4,5-c]quinolin-4-amine, which was isolated an off-white powder, mp 205-208° C. The product was not recrystallized.
Reaction SMILES: C1(S([C:10]([F:22])([F:21])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)C=CC=CC=1>CO>[F:21][CH:10]([F:22])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)C(F)(F)CCCCc1ccccc1
Solvent: CO
Product: FC(F)CCCCc1ccccc1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Typical Procedures for the Preparation of Difluoromethyl Alkanes (11) from Alkyl-substitued Difluoromethyl Sulfones (4): Under an argon atmosphere, into a Schlenk flask containing 1,1-difluoro-5-phenylpentyl phenyl sulfone (4h) (100 mg, 0.31 mmol), anhydrous Na2HPO4 (308 mg, 2.2 mmol) in methanol (4 mL) at −20° C., was added 5% Na/Hg amalgam beads (700 mg, ca. 1.5 mmol Na). The reaction mixture was stirred at −20° C.˜0° C. for 1 h, and the completion of the reaction was monitored by 19F NMR. The methanol solution was decanted out, and the residue solids were washed with Et2O (5 mL×3). The volatile solvents of the combined solution were removed under vacuum, and the crude product was purified by a flash chromatography to give 1,1-difluoro-5-phenylpentane (11a) (50 mg, 87% yield) as a colorless liquid. 1H NMR (500 MHz, CDCl3): δ 1.51 (m, 2H); 1.70 (m, 2H); 1.86 (m, 2H); 2.64 (t, J=7.7 Hz, 2H); 5.80 (tt, J=57 Hz, 4.7 Hz, 1H); 7.19 (m, 3H); 7.30 (t, J=7.6 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 21.7 (t, J=5.4 Hz); 30.8; 33.9 (t, J=21 Hz); 117.3 (t, J=239 Hz); 125.8; 128.3; 141.9. 19F NMR (470 MHz, CDCl3): δ −116.2 (dt, J=57 Hz, 18 Hz, 1F).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.Cl[CH:12](Cl)[O:13]C>ClCCl.Cl[Ti](Cl)(Cl)Cl>[OH:10][C:5]1[C:4]2[CH2:3][CH2:2][CH2:1][C:9]=2[C:8]([CH:12]=[O:13])=[CH:7][CH:6]=1
Reactant: COC(Cl)Cl
Reactant: Oc1cccc2c1CCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(O)c2c1CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2,3-dihydro-1H-inden-4-ol (3.0 g, 22.36 mmol, 1.00 equiv) in dichloromethane (20 ml) and TiCl4 (7.66 g, 40.38 mmol, 1.80 equiv). After 5 minutes, dichloro(methoxy)methane (2.81 g, 24.44 mmol, 1.10 equiv) was added at 0° C. in a water/ice bath and the resulting solution stirred for 3 h at 0° C. The reaction was then quenched by the addition of 25 mL of water. The resulting solution was extracted with 2×150 mL of dichloromethane. The organic layers were combined, washed with 1×50 mL of H2O, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2.3). This resulted in 1.26 g (35%) of 7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C10H10O2, 163.1 (M+H). found 163.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-Bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (CAS: 201940-08-1) and pyrrolidine. Orange solid. MS (m/e): 289.2 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+].O>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([C:14](=[N:18][OH:19])[CH3:15])=[CH:10][C:3]=1[CH2:4][NH:5][C:6](=[O:9])[O:7][CH3:8]
Reactant: NO
Reactant: COC(=O)NCc1cc(C(C)=O)ccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COC(=O)NCc1cc(C(C)=NO)ccc1Cl
Yield: 97.9 %

Procedure:
5.0 g of methyl N-(2-chloro-5-acetylbenzyl)carbamate was dissolved in 10 ml of ethanol, and 1.5 g of hydroxylamine hydrochloride, 3.0 g of sodium acetate and 5 ml of water were added thereto, followed by reflux under heating for 4 hours. After completion of the reaction, water was added to the reaction mixture, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane to obtain 5.2 g of methyl N-[2-chloro-5-(1-hydroxyiminoethyl)benzyl]carbamate as colorless crystals (m.p. 124-127° C.).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CCOCC.[BrH:34].BrBr>C(O)(=O)C.C(Cl)Cl>[Br:34][C@@H:19]1[CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17][C:18]1=[O:28]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](Br)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
50 g. of 5α-cholestan-3-one is dissolved in 750 ml. of acetic acid and 5000 ml. of ether, combined with 1 ml. of hydrobromic acid in acetic acid (37% strength), and gradually added dropwise to a solution of 22 g. of bromine in 50 ml. of acetic acid. The mixture is agitated for another 30 minutes, diluted with methylene chloride, and washed in succession with water, sodium bicarbonate solution, and water. After drying and evaporation, 61.5 g. of crude 2α-bromo-5α-cholestan-3-one is obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)#[N:8].O.[OH-].[Na+]>C(OCC)C>[NH2:8][CH2:7][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(CO)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCc1ccc(CO)cc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a stirred suspension of LiAlH4 (285 mg, 7.52 mmol) in diethylether (10 mL)at 0° C. was added a solution of 4-cyanobenzyl alcohol (0.5 g, 3.76 mmol) in diethylether (5 mL) over 15 min. The grey reaction mixture was heated to reflux for 3 h. After cooling to r.t., the mixture was treated successively with water (1 mL), 2M NaOH (2 mL) and water (2 mL) under vigorous stirring. The resulting white slurry was filtered and washed with CH2Cl2 (20 mL). Extraction with additional CH2Cl2 (20 mL) and n-butanol (20 mL) and evaporation yielded an oil, which upon flash chromatography (0-15% MeOH in CH2Cl2) gave 152 mg (29%)of 4-(aminomethyl)benzylalcohol (57MBT52B) as a white solid. Rf=0.51 (30% MeOH in CH2Cl2+3.5% NH4OH).
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]2[C:3]=1[C:4]([OH:22])=[C:5]1[C:10](=[C:11]2[OH:19])[C:9](=[O:20])[CH2:8][CH2:7][C:6]1=[O:21].[F:23][C:24]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]2[C:25]=1[C:26](=[O:37])[O:27][C:28]2=O>>[F:1][C:2]1[C:3]2[C:12](=[C:11]([OH:19])[C:10]3[C:9](=[O:20])[C:8]4[C:7]([C:6](=[O:21])[C:5]=3[C:4]=2[OH:22])=[C:28]([OH:27])[C:29]2[C:25](=[C:24]([F:23])[C:32]([F:33])=[C:31]([F:34])[C:30]=2[F:35])[C:26]=4[OH:37])[C:13]([F:18])=[C:14]([F:17])[C:15]=1[F:16]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: O=C1CCC(=O)c2c1c(O)c1c(F)c(F)c(F)c(F)c1c2O
Product: O=C1c2c(c(O)c3c(F)c(F)c(F)c(F)c3c2O)C(=O)c2c1c(O)c1c(F)c(F)c(F)c(F)c1c2O

Procedure:
For example, 5,6,7,8-tetrafluoro-9,10-dihydroxy-2,3-dihydroanthracen-1,4-dione (1) is reacted with 4,5,6,7-tetrafluoroisobenzofuran-1,3-dione (2) to give 1,2,3,4,8,9,10,11-octafluoro-5,7,12,14-tetrahydroxypentacen-6,13-dione (3) (scheme 5). In addition, 5,7,12,14-tetrahydroxypentacen-6,13-dione (6) can be obtained from 9,10-dihydroxy-2,3-dihydroanthracen-1,4-dione (4) and isobenzofuran-1,3-dione (5) (scheme 6).
Reaction SMILES: [FH:1].[FH:2].F.C(N(CC)CC)C.C(N(CC)CC)C.[B-](F)(F)(F)F.CCN([S+](F)F)CC.[Cl:31][C:32]1[N:37]=[C:36]([N:38]([CH:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)[C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[CH3:40])[C:35]([N+:52]([O-:54])=[O:53])=[CH:34][N:33]=1>ClCCl>[Cl:31][C:32]1[N:37]=[C:36]([N:38]([CH:45]2[CH2:50][CH2:49][C:48]([F:2])([F:1])[CH2:47][CH2:46]2)[C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[CH3:40])[C:35]([N+:52]([O-:54])=[O:53])=[CH:34][N:33]=1
Reactant: F
Reactant: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(=O)CC1
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 69.4 %

Procedure:
To a stirred solution of triethylamine trihydrofluoride (2.72 mL, 16.7 mmol) and triethylamine (1.17 mL, 8.41 mmol) in dichloromethane (30 mL) was added Xtalfluor-E (2.9 g, 12.6 mmol) at 0° C. To the solution was then added methyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-(4-oxocyclohexyl)-D-alaninate (3 g, 8.37 mmol) slowly. An additional amount of Xtalfluor-E (2.9 g, 12.6 mmol) was added after 3 h, and resulting mixture was stirred at rt for 9 h. The reaction mixture was quenched with a 5% aqueous NaHCO3 solution. The resulting mixture was extracted with dichloromethane (40 mL×3). The organic phases were combined, dried over Na2SO4, evaporated to give the crude material, which was then purified by silica gel column chromatography to give the desired product (2.2 g). 1HNMR (300 MHz, CDCl3): δ 1.60-1.99 (m, 6H), 2.19-2.24 (m, 3H), 3.16-3.25 (m, 3H), 3.75 (s, 3H), 4.06 (q, J=6.9 Hz, 1H), 8.65 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH3:10])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH3:10])=[C:4]([C:11]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[O:13])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1c(C(=O)O)cc(Br)c(=O)n1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCN(C)CC2)cc(Br)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-1,2-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (70 mg, 0.284 mmol), 1-methylpiperazine (28.5 mg, 0.284 mmol), Et3N (0.1 mL) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (108 mg, 0.284 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was subsequently purified via preparative HPLC, eluting with a gradient of 20-70% ACN in H2O (containing 10 mM NH4HCO3) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:10][C:9]([F:12])([F:11])[C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)=[CH:3][CH:4]=1)[OH:13]
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: OB(O)c1cccc(F)c1
Product: O[C@H](c1ccc(-c2cccc(F)c2)cc1)C(F)(F)F

Procedure:
Similar to the above procedure, the title compound was prepared from (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (2) and 3-fluorophenylboronic acid. 1H NMR (CDCl3): δ 7.62 (d, J=6.0 Hz, 2H), 7.56 (d, J=6.3 Hz, 2H), 7.42 (m, 2H), 7.28 (m, 1H), 7.06 (m, 1H), 5.82 (q, J=5.1 Hz, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[CH:24]=[CH:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[OH-].[K+].O>CO>[OH:4][C@@H:5]1[CH:24]=[CH:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@@H]1C=C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)C=C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of crude 3α-acetoxy-5α-pregn-1-ene-11,20-dione (3.6 g.) in dry methanol (96 ml.) was treated with a solution of potassium hydroxide (650 mg.) in methanol (72 ml.), and the mixture stirred under nitrogen at room temperature for 2 hr. The reaction mixture was poured into water, and the product extracted with methylene chloride. The extract was washed with water, dried (MgSO4), and evaporated in vacuo. The residue (3.1 g.) was subjected to preparative t.l.c. The more polar product afforded the title compound (1.66 g.), with an RF identical on t.l.c. to that of the product of (a).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([S:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH2:3]1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)Cl>[Br:27][C:17]1[CH:18]=[C:13]([CH2:12][S:9]([N:4]2[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]2)(=[O:11])=[O:10])[CH:14]=[CH:15][C:16]=1[NH2:19]
Reactant: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)cc2)C[C@H](C)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc(N)c(Br)c2)C[C@H](C)N1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A solution of 283 mg (0.999 mmol) of 4-(cis-3,5-dimethyl-piperazine-1-sulfonylmethyl)-phenyl amine (as prepared in the previous step) in CH2Cl2 (15 mL) was cooled to −78° C. and treated portionwise with 176 mg (0.989 mmol) of NBS. The mixture was stirred at −78° C. for 1 h and at RT for 2 h. The mixture was diluted with CH2Cl2 (15 mL) and washed with saturated aqueous NaHCO3 (1×20 mL) and brine (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 356 mg (98%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C13H20N3O2SBr, 362.0/364.0 (M+H). found 361.8/363.3.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.Br[C:13]1[N:14]=[CH:15][S:16][CH:17]=1>>[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][O:10][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH2:6][O:5]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Brc1cscn1
Agent: [H-]
Agent: [Na+]
Product: CC1(C)OCC(COc2cscn2)O1

Procedure:
NaH (60% dispersion in mineral oil, 12.19 g, 305.3 mmol) was added portionwise to DL-1,2-isoproylideneglycerol (16.11 g, 1218 mmol) and the mixture was stirred until gas evolution had ceased (ca. 30 min RT, followed by 2 h at 60° C.). Subsequently, 4-bromothiazole (20.00 g, 121.9 mmol) was added and the mixture was stirred at 140° C. for 45 min. Subsequently, the reaction mixture was quenched with aq. sat. NH4Cl and extracted with EtOAc. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was subjected to distillation and the volatiles (HV, 60° C.) were removed. The residue was purified by means of CC (5-40% EtOAc/Hept) to provide a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH2:26](OCC)C.[N+](=C)=[N-].C(OC(C)C)(C)C>C(OCC)(=O)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([O:24][CH3:26])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Yield: 77 %

Procedure:
In 2 ml of ethyl acetate was dissolved 100 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, and a diethyl ether solution containing 15 mg of diazomethane was added thereto with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, acetic acid was added to the reaction mixture until foaming was not caused in the reaction mixture. The solvent was then removed by distillation under reduced pressure and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 80 mg (yield 77.0%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 18.