Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:27])[CH:10]2[NH:14][C:15](=[O:26])[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[S:22]([CH3:25])(=[O:24])=[O:23])[C:7]=1[C:28]([O:30]C(C)(C)C)=[O:29])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:27])[CH:10]2[NH:14][C:15](=[O:26])[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[S:22]([CH3:25])(=[O:24])=[O:23])[C:7]=1[C:28]([OH:30])=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cn3ccnc3S(C)(=O)=O)C2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3ccnc3S(C)(=O)=O)C2SC1
Reaction time: 3 h
Yield: 74.8 %

Procedure:
3-Acetoxymethyl-2-(tertiary butoxycarbonyl)-7-[(2-mesyl-imidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (6 g.) is dissolved in trifluoroacetic acid (60 cc.). The reagents are contacted for 3 hours while keeping the temperature at about 4° C. The mixture is then concentrated to dryness under reduced pressure (1 mm.Hg) at 40° C., and the residue is recrystallised from acetonitrile (15 cc.) to give 3-acetoxymethyl-2-carboxy-7-[(2-mesyl-imidazol-1-yl)-acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (4 g.), m.p. 223° C., [α]D20 = 78.9° ± 1.5° (c= 1, dimethylformamide).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:20][N:21]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[CH:24][C:23]([C:34](Cl)=[O:35])=[N:22]1>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:34]([C:23]1[CH:24]=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[N:21]([CH2:20][C:19]2[CH:37]=[CH:38][C:39]([CH3:40])=[C:17]([Cl:16])[CH:18]=2)[N:22]=1)=[O:35]
Reactant: CC1CCCCC1N
Reactant: Cc1ccc(Cn2nc(C(=O)Cl)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(C(=O)NC3CCCCC3C)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 36 from 1 ml of 2-methylcyclohexylamine, 1 ml of triethylamine in 15 ml of DCM and 1.5 g of the compound obtained in step A of EXAMPLE 36 in 15 ml of DCM. The compound is purified by chromatography on silica using a DCM/MeOH mixture (98/2; v/v) as the eluent to give 0.27 g of the expected product. M.p.=165° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[OH:48][C@@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@@H](O)CC2)C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(cis-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. Purification: ISCO Combi-flash Rf system, eluting with 0 to 5% MeOH in EtOAc. 1H NMR (400 MHz, DMSO-d6) δ10.56 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 7.47 (br. s., 1H), 7.29 (d, J=8.34 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J=8.08 Hz, 1H), 4.49 (s, 2H), 4.40 (d, J=4.80 Hz, 1H), 3.95-4.07 (m, 4H), 3.91 (br. s., 1H), 3.75 (s, 3H), 3.07 (s, 3H), 1.84-1.97 (m, 2H), 1.77 (d, J=12.38 Hz, 2H), 1.43-1.61 (m, 4H), 1.20 (t, J=6.95 Hz, 6H); MS (ES+): m/z: 678.24 [MH+]. HPLC: tR=3.52 min (ZQ3: polar—5 min).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[O:18][CH:19]=2)=[CH:9][C:8]=1[CH3:28])C.[Li+].[OH-]>>[CH2:30]([O:29][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[O:18][CH:19]=2)=[CH:9][C:8]=1[CH3:28])[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCc2coc(-c3cccc(OC)c3)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2coc(-c3cccc(OC)c3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-2-ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{4-[2-(3-methoxy-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless liquid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:24][O:25][NH:26][CH3:27]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:26]([O:25][CH3:24])[CH3:27])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)c(Br)c1
Reaction time: 8 h

Procedure:
A solution of 3-bromo-4-fluorobenzoic acid (100 g, 0.456 mol) and CDI (77.2 g, 0.547 mol) in 1 L of dry DCM was stirred at r.t. for 30 min and then O,N-dimethyl-hydroxylamine (53.4 g, 0.547 mol) was added. The resulted mixture was stirred overnight. The solvents were removed under vacuum and the residue was purified via column chromatograph to afford 3-bromo-4-fluoro-N-methoxy-N-methylbenzamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.[CH:24](=O)[CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]([C:12]([N:9]2[CH2:10][CH2:11][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8]2)=[O:13])[CH2:15][CH2:16]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C(N1CCC(c2cccnc2)C1)N1CCNc2ccccc21
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCN1CCN(C(=O)N2CCC(c3cccnc3)C2)c2ccccc21

Procedure:
0.2 g of 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline, dissolved in 22 ml of dichloromethane, is introduced into a 100 ml round-bottomed flask. 0.29 ml of N-butyraldehyde is subsequently added, followed by 0.27 g of sodium triacetoxyborohydride, and the reaction mixture is stirred for eighteen hours. A saturated aqueous sodium hydrogencarbonate solution is added and then the aqueous phase is extracted three times with dichloromethane. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 95/5 mixture. 0.032 g of 1-butyl-4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)=[C:5]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=1.Cl.[NH2:30][CH:31]1[CH2:37][CH2:36][C:35](=[O:38])[NH:34][C:32]1=[O:33]>N1C=CC=CC=1>[O:33]=[C:32]1[CH:31]([N:30]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]2=[O:15])[CH2:37][CH2:36][C:35](=[O:38])[NH:34]1
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)c(Oc2ccccc2)c1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c(Oc2ccccc2)c1
Yield: 89 %

Procedure:
A mixture of 3-(4-methoxy-2-phenoxy-phenylamino)-phthalic acid (0.60 g, 1.6 mmol) and rac-α-aminoglutarimide hydrochloride (0.26 g, 1.6 mmol) in pyridine (10 mL) were heated to reflux for 20 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute aqueous HCl (3×100 mL) and water (100 mL), and then evaporated under vacuum. The residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 0.66 g of the product, an orange solid, at 95:5 methylene chloride-methanol, in 89% yield: mp 142-144° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 4.71 min (96.79%); 1H NMR (DMSO-d6) δ 1.98-2.04 (m, 1H), 2.49-2.61 (m, 2H), 2.81-2.90 (m, 1H), 3.73 (s, 3H), 5.06 (dd, J=12.8 Hz, J=5.3 Hz, 1H), 6.58 (d, J=2.8 Hz, 1H), 6.84 (dd, J=8.8, J=2.8 Hz, 1H), 6.90-6.94 (m, 2H), 7.04-7.10 (m, 2H), 7.16 (d, J=7.0 Hz, 1H), 7.27-7.34 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.3 Hz, J=7.4 Hz, 1H), 7.95 (s, 1H), 11.10 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 30.9, 48.6, 55.5, 105.9, 109.6, 110.7, 112.6, 117.9, 118.7, 122.8, 123.5, 127.2, 129.9, 132.0, 136.0, 144.0, 151.1, 156.2, 157.8, 167.1, 168.5, 169.9, 172.8; Anal. calcd For C26H21N3O6.0.3H2O: C, 65.49; H, 4.55; N, 8.84. Found: C, 65.43; H, 4.29; N, 8.73.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
4-Phenoxybenzenamine (18.5 grams; 0.1 mole) and pyridine (50 ml) were charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and cooled to about 4° C. Ethyl chloroformate (13.5 grams; 0.125 mole) was added and the reaction stirred at about 4° C. for a period of about 30 minutes, stirring was then continued at room temperature for another 16 hours. Crystallization occured, whereupon the precipitate was filtered from the reaction medium, washed with water, and air dried to give the desired product ethyl (4-phenoxyphenyl)carbamate.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(Cl)cc(-c3ccc(OC(C)C)cc3)nc2c1
Temperature: 90 °C
Yield: 85.1 %

Procedure:
To a degassed solution of 2,4-dichloro-7-methoxyquinoline (1 g, 4.3 mmol) in dioxane/water (8:2) was added 4-isopropoxyphenylboronic acid (870 mg, 4.82 mmol) followed by potassium carbonate (1.2 g, 8.7 mmol) and Pd(PPh3)4 (253 mg, 0.22 mmol) at room temperature under nitrogen atmosphere. The reaction mass was heated at 90° C. for 18 h. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to afford 4-chloro-2-(4-isopropoxyphenyl)-7-methoxyquinoline (1.2 g, 85%) as off white solid. MS: MS m/z 328.7 (M++1).
Reaction SMILES: [CH3:1][N:2](C(CN)=O)[C@@H:3]1[C@@H:8]([O:9][CH3:10])[C@@H:7]([OH:11])[C@H:6]([NH2:12])[C@@H:5]([O:13][C@H:14]2[O:19][C@H:18]([CH2:20][NH2:21])[CH2:17][CH2:16][C@H:15]2[NH2:22])[C@@H:4]1[OH:23].[OH-].[Na+].[OH-].[Ba+2].[OH-].C(=O)=O>>[CH3:1][NH:2][C@@H:3]1[C@@H:8]([O:9][CH3:10])[C@@H:7]([OH:11])[C@H:6]([NH2:12])[C@@H:5]([O:13][C@H:14]2[O:19][C@H:18]([CH2:20][NH2:21])[CH2:17][CH2:16][C@H:15]2[NH2:22])[C@@H:4]1[OH:23]
Reactant: CO[C@H]1[C@@H](O)[C@H](N)[C@@H](O[C@H]2O[C@H](CN)CC[C@H]2N)[C@H](O)[C@@H]1N(C)C(=O)CN
Agent: O=C=O
Agent: [Ba+2]
Agent: [Na+]
Product: CN[C@H]1[C@@H](O)[C@H](O[C@H]2O[C@H](CN)CC[C@H]2N)[C@@H](N)[C@H](O)[C@@H]1OC

Procedure:
Fortimicin KE may also be obtained by heating Fortimicin D in an alkaline aqueous solution such as sodium hydroxide and barium hydroxide. Specifically, Fortimicin D is heated in an aqueous solution of saturated barium hydroxide at a temperature of 100° C. for 3 hours. Then the reaction solution is neutralized with dry ice and the resulting precipitate of barium carbonate is removed by filtration. The filtrate is concentrated and passed through a column packed with Amberlite CG-50 (ammonium form). After washing the column with water, elution is carried out with 0.2 N aqueous ammonia. First, a small amount of reaction by-products is eluted and subsequently Fortimicin KE is eluted. The fractions containing Fortimicin KE are combined and concentrated under reduced pressure. The concentrate is then freeze-dried to obtain the free base of Fortimicin KE.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]([NH2:36])[C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4].[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(CC)CC>CN(C=O)C.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]([NH:36][C:41]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[O:48])[C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1cccnc1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)ccc(N)c2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)ccc(NC(=O)c3cccnc3)c2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Yield: 76.9 %

Procedure:
A solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-3-aminophenyl)urea (300 mg, 0.485 mmol), nicotinic acid (66 mg, 0.533 mmol), 1-hydroxybenzotriazole (131 mg, 0.97 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (93 mg, 0.485 mmol) and Et3N (0.06 ml, 0.485 mmol) in DMF (10 ml) is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with an aqueous ammonium chloride solution, and washed twice with an aqueous sodium hydrogen carbonate solution. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (243 mg, 0.373 mmol) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.Cl.C[N:22](C)[CH2:23][CH2:24]CN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N)C>O1CCCC1.C(Cl)(Cl)Cl.O>[CH2:23]([NH:22][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:4]=1)[CH3:24]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 24 h
Yield: 94.8 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.3 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g) and 3H-[1,2,3] 1-hydroxy-7-azabenzotriazole (0.077 g) was added to a stirred solution of ethylamine in tetrahydrofuran (2M, 5 ml) in chloroform (30 ml) and the mixture was stirred for 24 h. The mixture was poured into water, passed through a hydrophobic filter tube and the organic phase was concentrated under vacuum. The residual solid was purified on an SCX cartridge eluting with methanol to give the title compound as a pale yellow solid (1.36 g).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@@H:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C@H:6]1[OH:25])[C:19]1[CH:18]=[CH:17][C:16]([O:23]C)=[CH:15][C:14]=1[CH2:13][CH2:12]3)[CH3:4].C1C=C[NH+]=CC=1.Br[Br-]Br.C(OCC)(=O)C.C(OC(C)C)(C)C>CO>[CH2:3]([C@@H:5]1[CH2:10][C@H:9]2[C@H:11]3[C:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C@H:6]1[OH:25])=[C:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)[CH3:4]
Reactant: CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Agent: [BH4-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)[C@H]1O
Yield: 51 %

Procedure:
According to 1(b), 20.2 g of 16α-ethyl-3-methoxy-1,3,5(10)-estratrien-17-one, N,N-dimethylhydrazone, m.p. 101°-103° C. (from acetonitrile) is obtained from 20.4 g of 3-methoxy-1,3,5(10)-estratrien-17-one N,N-dimethylhydrazone after metallization and alkylation with 9.2 ml of bromoethane. By reaction with CuCl2.2H2O according to 1(c), the 17-ketone is obtained from the hydroazone and then, by reduction of the 17-ketone with sodium borohydride according to 1(d), 16.0 g of 16α-ethyl-3-methoxy-1,3,5(10)-estratrien-17β-ol, m.p. 75°-76° C. (from methanol) is prepared. 10.0 g of 16α-ethyl-3-methoxy-1,3,5(10)-estratrien-17β-ol is subjected analogously to 1(e) in succession to Birch reduction, acid hydrolysis, and reaction with pyridine hydrobromide perbromide, thus obtaining 7.8 g of 16α-ethyl-17β-hydroxy-4,9(10)-estradien-3-one, m.p. 132°-135° C. (from ethyl acetate/diisopropyl ether). This product is converted analogously to 1(f) with acetic anhydride/pyridine into the 17-acetate, m.p. 124°-126° C. (from ether) and analogously to 1(g) by ketalization and subsequent ketal cleavage into the 17β-acetoxy-16α-ethyl-5(10),9(11)-estradien-3-one.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][CH3:24])[CH:17]=1)=[CH:12][C:11]([S:25]([CH2:28][CH2:29][C:30]([OH:32])=O)(=[O:27])=[O:26])=[CH:10][C:9]=2[CH3:33])=[O:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[ClH:1].[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:13]3[C:8](=[C:9]([CH3:33])[CH:10]=[C:11]([S:25]([CH2:28][CH2:29][C:30]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:32])(=[O:26])=[O:27])[CH:12]=3)[N:7]=[CH:6][C:5]=2[C:3]([NH2:2])=[O:4])=[CH:17][C:18]=1[O:23][CH3:24]
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCC(=O)O)cc23)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCC(=O)N4CCOCC4)cc23)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Example 481 (0.035 g) in N,N-dimethylformamide (2 ml) was added O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.029 g). After 5 min, morpholine (0.007 ml, available from Aldrich) and N,N-diisopropylethylamine (0.026 ml) were added. The resulting solution was stirred at room temperature overnight, and applied directly to an SCX cartridge (IST Isolute™, 5 g). Elution with methanol and 2M ammonia/methanol gave an orange residue, which was further purified by mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.006 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.B([C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)(O)O>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)s1

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol and 5-boronothiophene-2-carboxylic acid. 1H NMR (CD3OD, 400 MHz): δ 8.25 (d, J=8.8 Hz, 1H), 7.97 (dd, J=9.2, 3.2 Hz, 2H), 7.88-7.82 (m, 2H), 7.41 (dd, J=9.2, 2.8 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H). MS (ESI): m/z 271.6 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:32](=[O:34])=[O:33]>C(OCC)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:32]([OH:34])=[O:33])[CH:7]=1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
3.00 g (0.0086 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 30 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 5.9 ml of a 1.6M-hexane solution of BuLi (0.0086×1.1 mol) was added thereto, followed by stirring the obtained solution for about 10 minutes. After an interior of reactor was replaced with carbon dioxide gas, the reaction solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=1)[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Product: COc1ccc(C(=O)N2C(=O)C(C)(C)c3cc(C4=NNC(=O)SC4C)ccc32)cc1OC
Yield: 19 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-3,3 dimethyl-2H-indol-2-one (Example 3) and following the method described in Example 23, but using 3,4-dimethoxy benzoyl chloride instead of isonicotinoyl chloride, afforded the desired compound.