Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)\[CH3:7])[CH3:2].[Br:21]N1C(=O)CCC1=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>ClCCl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[CH:13][CH:14]=1)\[CH2:7][Br:21])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccc(CC(C)(C)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C(\CBr)Oc1ccc(CC(C)(C)O)cc1

Procedure:
A solution of (E)-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (0.500 g, 1.80 mmol) in dichloromethane (40 mL) was treated with N-bromosuccinimide (0.350 g, 1.97 mmol) and 2,2′-azobis(2,4′-dimethylvaleronitrile) (0.045 g, 0.18 mmol) under nitrogen. The mixture was then refluxed for 5 h, cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) to afford the intermediate (E)-4-bromo-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester. A solution of (E)-4-bromo-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester in acetonitrile (20 mL) was immediately treated with (L)-leucine methyl ester hydrochloride (0.21 g, 2.17 mmol) and N,N-diisopropylethylamine (0.510 g, 3.95 mmol). The resulting mixture was sealed in a tube and heated at 90° C. overnight and then cooled and partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (approximately 5 mL) and heated at 160° C., for 6 h in a sealed tube. At this time, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 30% to 100% ethyl acetate/hexanes) to afford, (S)-2-{4-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (0.180 g, 27%) as a waxy off-white solid.
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[H-].[Na+].BrC[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1.O>O1CCCC1>[CH3:1][CH:2]([CH2:8][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1nc(-c2ccccc2)nc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Reaction time: 1 h
Yield: 41.3 %

Procedure:
A solution of diethyl methylmalonate (23 g) in anhydrous tetrahydrofuran (100 cc) is added under nitrogen to sodium hydride (4 g, 80% strength in oil) and anhydrous tetrahydrofuran (60 cc). After 1 hour's stirring, a solution of 4-bromomethyl-2-phenylquinazoline (9.9 g) in anhydrous tetrahydrofuran (100 cc) is added, and the mixture is stirred for a further 2 hours at room temperature (approximately 20° C.). Water (100 cc) is added and the mixture is extracted with ethyl acetate (3×100 cc). The organic phase is dried over magnesium sulphate and then evaporated to dryness under reduced pressure. The residue is taken up in concentrated hydrochloric acid (100 cc) and acetic acid (100 cc) and the mixture is brought to 110° C. for 24 hours. After the mixture has cooled, the precipitate is filtered off and washed with water and then ispropyl ether. After being dried, α-methyl-2-phenyl-4-quinazolinepropanoic acid (4 g), m.p. 180° C., is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[N:12]([C:13]=1[C:14](=O)[CH2:15]COC)[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:3]C)=O.O.[NH2:21][NH2:22].[CH2:23]([OH:25])C>>[CH3:23][O:25][CH2:15][C:14]1[C:13]2[N:12]3[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]3)=[CH:6][C:5]=2[C:1](=[O:3])[NH:22][N:21]=1
Reactant: NN
Reactant: COCCC(=O)c1c(C(=O)OC)cc2ccccn12
Reactant: CCO
Solvent: O
Product: COCc1n[nH]c(=O)c2cc3ccccn3c12
Yield: 97 %

Procedure:
A mixture of (IV) [7.06 g, 30.5 mmol] and excess 85% hydrazine hydrate in ethanol (300 mL) was heated under reflux (a precipitate formed). After cooling, the solid was collected by filtration and dried to give 4-methoxymethylpyridazino[4,5-b]indolizin-1-one (V, 6.81 g, 97%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(O)(=O)CC(O)=O.C([K])C.[CH2:21]([O:23][C:24](=[O:35])[CH2:25]C(C1C(F)=CC=CN=1)=O)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:35])[CH2:25][C:8]([C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH3:22]
Reactant: O=C(O)c1nccnc1Cl
Reactant: CCOC(=O)CC(=O)c1ncccc1F
Agent: CC[K]
Agent: O=C(O)CC(=O)O
Product: CCOC(=O)CC(=O)c1nccnc1Cl
Yield: 39.54 %

Procedure:
3-(3-Chloro-pyrazin-2-yl)-3-oxo-propionic acid ethyl ester (12) (2 g, 39.54%) was synthesized as a yellow liquid from 3.5 g of 3-chloro-pyrazine-2-carboxylic acid (11) and 5.64 g of ethyl potassium malonate (2) following the procedure described for 3-(3-fluoro-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (3).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.IC.[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:22])=[O:16])=[CH:18][CH:19]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A mixture of 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzoic acid (572 mg, 2.20 mmol), iodomethane (140 μL, 2.24 mmol), and cesium carbonate (710 mg, 2.17 mmol) in 6 mL of DMF was stirred at rt for 16 h. The mixture was diluted with H2O (10 mL) and extracted with Et2O (100 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40S cartridge using 3:17 v/v EtOAc/hexanes as the eluant afforded 399 mg (72%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][Si](C)(C)C)[CH:5]=[O:6].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31](C=CC2C=C(OC)C(OC)=C(OC)C=2)=O)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].C(N(CC)CC)C.CN(C=[O:58])C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[I:1][C:2]1[C:9]([OH:10])=[C:8]([O:15][CH3:16])[CH:7]=[C:4]([C:5](=[O:6])[CH2:31][CH2:30][C:29]([C:21]2[CH:20]=[C:19]([O:18][CH3:17])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=2)=[O:58])[CH:3]=1
Reactant: COc1cc(C=O)cc(I)c1O[Si](C)(C)C
Reactant: COc1cc(C=CC(=O)C=Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reactant: CN(C)C=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 3-iodo-4-trimethylsilyloxy-5-methoxybenzaldehyde in 570 mL of seive dried DMF was added 3,4,5-trimethoxyphenylvinyl ketone from Example 1, Step B (179 g, 0.805 mole) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (61.9 g, 0.24 mole). Triethylamine (320 mL) was added, and the resulting mixture was stirred at 70° C. under nitrogen atmosphere for 2 hours. The mixture was cooled, filtered, and washed with MeOH (500 mL). The resulting solution was cautiously acidified with 6 N HCL to pH 1.5 and a heavy yellow precipitate began to form. This mixture was stirred at room temperature for 2 hours to ensure complete desilylation. The precipitate was filtered, washed with H2O (4×1 L), and redissolved in a minimum volume of CH2Cl2. The solution was washed with brine, dried over anhydrous MgSO4, and evaporated in vacuo to provide a white solid. The solid was washed with MeOH and dried under high vacuum to provide 1-(5-iodo-4-hydroxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione as a white solid, m.p. 189°-190° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[O:27][CH3:28])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:42](=[O:43])[CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:27][CH3:28])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
A suspension of 0.250 g of 7β-amino-3 -methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 25 ml of methylene chloride is treated with 1 ml of pyridine and 0.5 ml of phenylacetic acid chloride at 0° C. under a nitrogen atmosphere and stirred for 30 minutes at this temperature. The reaction mixture is evaporated under reduced pressure; the residue is stirred for 10 minutes with 20 ml of a 1:1 mixture of dioxane and water and the mixture is diluted with methylene chloride. The aqueous phase is separated off and extracted with methylene chloride. The combined organic phases are washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The crude product is purified by means of preparative thin layer chromatography, using a 1:1 mixture of toluene and ethyl acetate as the solvent. The zone visible under ultraviolet light of λ=254 mμ (Rf~0.35) is eluted with a 4:1 mixture of acetone and methanol and yields 3-methoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, which is identical with the product obtainable according to the process of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][N:8]=1.O=P(Cl)(Cl)[Cl:23]>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([Cl:23])=[N:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCCc1n[nH]c(=O)c2cc(OC)ccc12
Solvent: CC#N
Product: COC(=O)CCCc1nnc(Cl)c2cc(OC)ccc12
Yield: 73.8 %

Procedure:
A suspension of 4-(6-methoxy-4-oxo-3,4-dihydro-phthalazin-1-yl)-butyric acid methyl ester (9.23 g, 0.034 moles), prepared as described in example 113, and POCl3 (1.87 ml, 0.2 mole) in acetonitrile (100 ml) was refluxed. After 1.5 hours the mixture was dried, taken up in water and neutralised with NaHCO3. The mixture was extracted with ethyl acetate and the organic phase dried to give a residue which was chromatographed (eluent: petrolatum/ethyl acetate 7:3). There were yielded 7.4 g of the title compound (yield: 63.9%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13][C:12]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.NN.[C:30](Cl)(=[O:32])[CH3:31]>CO.C(Cl)Cl.N1C=CC=CC=1.[Ni]>[C:17]([C:16]1[C:11]([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[C:12]([C:19]2[CH:20]=[C:21]([NH:25][C:30](=[O:32])[CH3:31])[CH:22]=[CH:23][CH:24]=2)[CH:13]=[N:14][CH:15]=1)#[N:18]
Reactant: N#Cc1cncc(-c2cccc([N+](=O)[O-])c2)c1Nc1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2cncc(C#N)c2Nc2ccc3[nH]ccc3c2)c1
Reaction time: 2 h

Procedure:
To a solution of 4-(1H-indol-5-ylamino)-5-(3-nitrophenyl)nicotinonitrile 151 (9 mg, 0.025 mmol) in MeOH (1 mL) were added hydrazine (20 uL) and Raney-Nickel (2-5 mg). The mixture was stirred for 2 h then filtered through celite and the filtrate was concentrated to give the crude reduced product which was then dissolved in CH2Cl2 (1 mL) and pyridine (20 uL), and acetyl chloride (20 uL) was added. After stirring for 1 h, the reaction mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (4 mg). MS: 366.0 (M+H), HPLC retention time: 1.61 min.(a).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)[N:10]3[CH:32]=[CH:33][N:34]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C([O-])(O)=O.[Na+].C(Cl)[Cl:41]>>[Cl:41][C:32]1[N:10]2[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:29][C:30]#[N:31])[CH2:21][N:20]([S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23])[CH2:19]4)[CH:17]=3)=[N:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][C:9]2=[N:34][CH:33]=1
Reactant: ClCCl
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(-c2cc3ncc(Cl)n3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C(F)(F)F)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
2-(3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (Example 96; 0.150 g, 0.305 mmol) was suspended in DCM (5 mL) and saturated aqueous NaHCO3 (2 mL). n-Chlorosuccinimide (0.204 g, 1.53 mmol) was added in one portion and the reaction mixture stirred at ambient temperature overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2-3% (9:1 MeOH:NH4OH)/DCM to provide 2-(3-(4-(3-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(trifluoromethylsulfonyl)azetidin-3-yl)acetonitrile (0.027 g, 0.051 mmol, 17% yield). MS (apci) m/z=526.0 (M+H).
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[Na].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:15]([O:14][C:6]([CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:19]([CH2:20][CH2:21][CH2:22][CH2:2][CH3:3])[CH3:18])=[O:13])[CH3:16]
Reactant: CC[O-]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCBr
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCCC(C)C(C(=O)OCC)C(=O)OCC
Temperature: 50 °C

Procedure:
Alcoholic sodium ethoxide, prepared from sodium (7.8 g, 0.34 mol) in super-dry ethanol (200 cm3) was cooled to ca. 50° C. and diethyl malonate (55 g, 0.34 mol) added slowly with vigorous stirring. 1-Bromopentane (49.5 g, 0.33 mol) was added gradually and the mixture refluxed until neutral to moist litmus (ca. 2 h). The solvent was removed in vacuo and water (200 cm3) added. The aqueous layer was extracted with diethyl ether (2×100 cm3) and the combined ethereal layers were dried (Na2SO4). The solvent was removed in vacuo and the pure product isolated by distillation under reduced pressure.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5].CC(C)([O-])C.[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1>>[CH3:1][CH:2]([O:6][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCCC(C)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 2-pentanol (3.65 mL) was added sodium tert-butoxide (760 mg) in portions over 5 mins. The mixture was stirred at room temperature until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) was added and the reaction was heated at 50° C. overnight, then for a further 72 h. The reaction mixture was cooled and quenched with water (10 mL) and was extracted with EtOAc (3×25 mL). The organics were combined, washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to give crude title compound as a viscous yellow oil.
Reaction SMILES: [CH3:1][Mg]Cl.[F:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15](=[O:17])[CH3:16].[NH4+].[Cl-]>CCCCCCC.C1COCC1>[F:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]([OH:17])([CH3:1])[CH3:16]
Reactant: COc1ccc(C(C)=O)c(F)c1OC
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methylmagnesium chloride (3M in THF, 1.74 mL, 5.22 mmol) was added dropwise to a stirred solution of 1-(2-fluoro-3,4-dimethoxyphenyl)ethanone (J. Chem. Soc. Perkin Trans. 2 1994, 547-555) (646 mg, 3.26 mmol) in heptane (3.1 mL) and THF (1.4 mL) at −20° C. under N2. The reaction was allowed to warm to room temperature and was stirred for 4 h. 50% Saturated NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol as a colorless oil. LCMS calc.=197.1; found=197.1 (M-OH)+. 1H NMR (600 MHz, CDCl3) δ 7.14 (t, J=8.8 Hz, 1H), 6.61 (dd, J=8.8, 1.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 2.56-2.25 (br s, 1H), 1.58 (s, 6H).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:40]([NH:43][CH3:44])([CH3:42])[CH3:41]>ClCCl.CN(C=O)C>[CH:28]([N:26]([CH3:27])[C:24]1[C:23]([C:31]([F:33])([F:34])[F:32])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:43]([CH:40]([CH3:42])[CH3:41])[CH3:44])=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CNC(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)N(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (220 mg, 0.47 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropylmethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (110 mg, 45%).
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]([C@:14]1([OH:34])[C@@:18]2([CH3:33])[CH2:19][CH2:20][C@@H:21]3[C@:31]4([CH3:32])[C:25](=[CH:26][C:27]([CH2:29][CH2:30]4)=[O:28])[CH2:24][CH2:23][C@H:22]3[C@@H:17]2[CH2:16][CH2:15]1)=[O:13]>C(Cl)(Cl)Cl.C(OCOCC)C>[OH:34][C@:14]1([C@:18]2([CH3:33])[C@H:17]([C@H:22]3[C@H:21]([CH2:20][CH2:19]2)[C@:31]2([CH3:32])[C:25](=[CH:26][C:27](=[O:28])[CH2:29][CH2:30]2)[C:24](=[CH2:1])[CH2:23]3)[CH2:16][CH2:15]1)[C:12](=[O:13])[CH3:11]
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCOCC
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 65 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A suspension of 1.0 g of sodium acetate in 30 ml of chloroform, 30 ml of formaldehyde diethylacetal, and 3.8 ml of phosphorus oxychloride is agitated in a two-necked flask for 1 hour at a bath temperature of 65° C. and then combined with 1.0 g of 17α-hydroxyprogesterone. The mixture is stirred for 1.5 hours at 65° C., cooled to room temperature, and under vigorous agitation a saturated soda solution is added dropwise until alkaline reaction occurs. The organic phase is separated, washed neutral with water, dried over sodium sulfate, and concentrated under vacuum. The crude product is purified on 220 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone), thus obtaining 842 mg of 17α-hydroxy-6-methylene-4-pregnene-3,20-dione, mp 218°-220° C.
Reaction SMILES: N[C:2]1[NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3O)[CH:9]=[N:10][C:5]2=[C:4]([OH:20])[N:3]=1.CC(OC(N(C)C)N(C)C)(C)C.C1(C)C=CC=CC=1>CN(C)C=O>[OH:20][C:4]1[N:3]=[CH:2][NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[CH2:12]3)[CH:9]=[N:10][C:5]=12
Reactant: Nc1nc(O)c2ncc([C@@H]3N[C@H](CO)[C@@H](O)[C@H]3O)c-2[nH]1
Agent: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)C[C@@H]1O
Temperature: 67.5 °C
Yield: 86.8 %

Procedure:
To a solution of the product from Example 1.2 (0.88 g) in N,N-dimethylformamide (5 ml) was added tert-butoxy bis(dimethylamine)methane (1.5 ml) and the solution was heated at 65-70° C. for 1 h. Toluene (20 ml) was added and the solution was washed (×3) with water, dried and concentrated to dryness. The residue was dissolved in tetrahydrofuran/acetic acid/water (1:1:1 v/v/v, 40 ml) at room temperature. After 1.5 h chloroform (50 ml) was added and the mixture was washed with water (×2), aqueous sodium bicarbonate, and then dried and evaporated to dryness Chromatography of the residue gave (1S)-N-tert-butoxycarbonyl-5-O-tert-butyldimethylsilyl-1-C-(1-cyano-2-hydroxyethenyl) -1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol (3) (0.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11]Cl)[CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1cccc(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-3-{[(2R)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: C([N:4]1[C:8]2[N:9]=[C:10]([Cl:14])[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[CH:5]1)C=C.C[N+]1([O-])CC[O:19]CC1.OO.[C:25]([OH:29])(C)([CH3:27])[CH3:26]>O.CO.O.O.[O-][Os]([O-])(=O)=O.[K+].[K+]>[Cl:14][C:10]1[NH:11][C:12](=[O:13])[C:7]2[CH:6]=[CH:5][N:4]([CH2:26][CH:25]([OH:29])[CH2:27][OH:19])[C:8]=2[N:9]=1
Reactant: C=CCn1ccc2c(=O)[nH]c(Cl)nc21
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1[nH]c(Cl)nc2c1ccn2CC(O)CO
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A mixture of 7-allyl-2-chloro-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate E, 40.8 mg, 195 μmol), 4-methylmorpholine N-oxide (11.4 mg, 97.3 μmol), and potassium osmate(VI) dihydrate (717 μg, 1.95 μmol) in tert-butanol (730 μL) and water (243 μL) cooled to 0° C. was treated with a 50% aqueous hydrogen peroxide solution (20 μL, 292 μmol). The reaction was allowed to warm to room temperature, where it stirred overnight. At this time, the reaction was diluted with methanol and absorbed onto Celite®. Flash chromatography (4 g silica gel column, 2-8% methanol/methylene chloride) afforded 2-chloro-7-(2,3-dihydroxy-propyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (16.4 mg, 34.6%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.57 (s, 1H) 3.80 (d, J=9.42 Hz, 1H) 3.85-3.99 (m, 1H) 4.14-4.29 (m, 1H) 4.75 (t, J=5.75 Hz, 1H) 4.98 (d, J=5.46 Hz, 1H) 6.46 (d, J=3.39 Hz, 1H) 7.12 (d, J=3.20 Hz, 1H) 12.80 (s, 1H). LC-MS calcd. for C9H11ClN3O3 [(M+H)+] 244, obsd. 243.9.