Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.O.[OH-].[Na+].CN([CH:22]=[O:23])C>>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:22]=[O:23])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
POCl3 (980 mg, 6.4 mmol) was added dropwise to DMF (3 mL) cooled in an ice bath. The mixture was stirred at 0° C. for 30 min before a solution of 6-bromo-1H-indole (1.0 g, 5.1 mmol) in DMF (7 mL) was slowly added at 0° C. The mixture was stirred at room temperature for 3 h before being poured into water and neutralized with 1N NaOH. The crude product was collected by filtration and used in next step without further purification. LCMS (m/z): 224.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:29][CH2:26][CH2:27][CH3:28])=[O:10])[CH:7]=1
Reactant: CCCN
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 51.3 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and n-propylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (207 mg, yield 51%). MS calcd for (C18H22BN3O5S): 403.1. MS found (ESI negative): (M−H)−=402.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 9.17 (bs, 1H), 7.99 (t, J=5.6 Hz, 1H), 7.42 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.46 (d, J=2 Hz, 1H)), 6.35 (d, J=8.8, 2.4 Hz, 1H), 4.87 (s, 2H), 3.78 (s, 2H), 3.05 (m, 2H), 1.43 (m, 2H), 0.85 (t, J=7.2 Hz, 3H).
Reaction SMILES: OC([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)NC=1)(C(O)=O)CC(=NO)C(O)=O.Cl.C(=O)([O-])[O-].[Na+].[Na+].O[C@](CC1C2C(=CC=CC=2)NC=1)(C(O)=O)CC(=[N:37]O)C(O)=O>O.C(OCC)(=O)C>[C:22]1([C@H:14]([NH2:37])[CH3:13])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C(C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Reactant: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After 44.7 g (0.131 mol) of the ammonium salt of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid was dissolved in 500 ml of water at 25° C., the resulting aqueous solution was adjusted to pH 2 using 25.5 g of 36% hydrochloric acid. The acidic solution was extracted in 1300 ml of ethyl acetate, and the resulting ethyl acetate solution was rinsed with 200 ml of aqueous saturated sodium chloride solution. 500 ml of an aqueous sodium carbonate solution (13.9 g (0.131 mole) of sodium carbonate) was added to the resulting ethyl acetate solution for agitation, to separate the aqueous alkali solution from ethyl acetate. 23.1 g of 36% hydrochloric acid was added to the resulting aqueous alkali solution, to adjust the solution to pH 2. 6.99 g (57.6 mmol) of(R)-(+)-1-phenylethylamine was added dropwise to the resulting aqueous acidic solution and the solution stirred at 25° C. for one hour. The resulting crystal was filtered and dried under reduced pressure, to obtain 21.8 g (47.8 mmol) of the (R)-(+)-1-phenylethylamine salt of (4S)-4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid. (Yield, 72.7%; optical purity, 87.4%.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH3:11].Cl.Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=N)OCC)[CH:17]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:9]([N:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:12][OH:13])=[CH:3][C:2]=2[N:1]=[C:22]1[C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH3:11]
Reactant: CCCNc1ccc(CO)cc1N
Reactant: CCOC(=N)c1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCn1c(-c2cccnc2)nc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
(a-4) A mixture of 8 parts of 3-amino-4-(propylamino)benzenemethanol, 14.05 parts of ethyl 3-pyridinecarboximidate dihydrochloride, 9.8 parts of sodium acetate and 96 parts of ethanol was stirred for 16 hours at room temperature. The reaction mixture was evaporated. The residue was dissolved in water and treated with ammonia. The precipitated product was filtered off, washed with water and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated. The residue was washed with 2,2'-oxybispropane, yielding 9.9 parts (84.1%) of 1-propyl-2-(3-pyridinyl)-1H-benzimidazole-5-methanol as a residue (interm. 4).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[CH:26][C:24](N)=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].N([O-])=[O:29].[Na+].C(O)(=O)C>>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[CH:26][C:24](=[O:29])[NH:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]
Reactant: Nc1ccn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1ccn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1

Procedure:
The derivative was synthesized via the unstable diazonium derivative starting with the commercially available 2′,3′-dideoxy-cytidine-5′-triphosphate (Boehringer Mannheim) by deamination with NaNO2/acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)c1
Temperature: 100 °C
Reaction time: 0.1 h

Procedure:
A mixture of 0.226 g (0.58 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.40 g (2.42 mmol) of 3-aminobenzoic acid, ethyl ester was fused in a 170° C. oil bath to give a clear melt. After 6 minutes, the melt was cooled to ca. 100° C. Glacial acetic acid (1 mL) was added to dissolve the melt. Water (5 mL) was added to precipitate a solid. The solid was filtered, washed well with water, and triturated with 2 mL of methanol. The mixture was filtered, and the cake was washed with 1 mL of methanol and then ether; wt 0.194 g. Recrystallization from ethyl acetate gave pure product; wt 0.075 g; mp 238°-240° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4].CCO>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1ncc2cc(C#Cc3ccccc3)ccc2c1O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2cc(CCc3ccccc3)ccc2c1O
Reaction time: 48 h
Yield: 569.4 %

Procedure:
A mixture of 4-hydroxy-7-phenylethynyl-isoquinoline-3-carboxylic acid methyl ester (60 mg, 0.20 mmol), 10% Pd/C (200 mg), EtOH (10 mL) and EtOAc (20 mL) was stirred under H2 atmosphere for 48 h. The resulting mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (0-40% EtOAc/hexanes) to give 350 mg of the title compound. MS: (+) m/z 308.26 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[C:15]([O:22][CH3:23])[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[C:15]([O:22][CH3:23])[CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cc(OC)c2cc[nH]c2c1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CCOC(=O)CC(c1ccccc1)c1cc(OC)c2cc[nH]c2c1

Procedure:
3-(4-Methoxy-1H-indol-6-yl)-3-phenyl-propionic acid ethyl ester CXXXV was prepared from 3-(4-methoxy-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][CH:8]1[O:12][CH:11]([C:13]2[CH2:14][S:15][C@@H:16]3[C@H:32]([NH:33]C(=O)CC4C=CC=CC=4)[C:31](=[O:43])[N:17]3[C:18]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:20])[CH2:10][CH2:9]1.CN1CCOCC1.CO>ClCCl.O>[NH2:33][C@@H:32]1[C:31](=[O:43])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[O:20])=[C:13]([C@@H:11]3[CH2:10][CH2:9][C@H:8]([CH3:7])[O:12]3)[CH2:14][S:15][C@H:16]12
Reactant: COc1ccc(COC(=O)C2=C(C3CCC(C)O3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(COC(=O)C2=C([C@@H]3CC[C@H](C)O3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
Phosphorus pentachloride (754mg, 3.62mmol) in dichloromethane (19ml) was added to 4-methoxybenzyl (6R,7R)-3-(5-methyltetrahydrofuran-2-yl)-7-phenylacetamidoceph-3-em-4-carboxylate (containing some of the Δ2-isomer) (1.26g, 2.41mmol) and N-methylmorpholine (531gl, 4.83mmol) in dichloromethane (15ml) at -25° C. The reaction was stirred at -10±5° C. for 45 min., then methanol (5ml) was added, and stirring was continued for 45 min. at room temperature. Water (10ml) was then added, and the mixture vigorously stirred for a further 1h. After evaporation of the dichloromethane in vacuo, the pH of the aqueous residue was adjusted to 7 by the addition of ammonium hydroxide in the presence of ethyl acetate. The mixture was extracted with ethyl acetate (x2), dried and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 30, 50, 70, 80 and 100% ethyl acetate in hexane yielding 4-methoxybenzyl (6R,7R)-7-amino-3-[(5S,2S)-5-methyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (310mg, 32%) as a pale yellow foam; (Found: M+, 404.1394. C20H24N2O5S requires M+ 404.1406); vmax (CH2Cl2) 3412, 1776, 1721, 1613, 1516 and 1393cm -1 ; δH (CDCl3, 250MHz), 1.24 (3H, d, J 5.8Hz), 1.48 (1H, m), 1.69 (1H, m), 2.02 (3H, m, 2H exch.), 2.25 (1H, m), 3.45 and 3.60 (2H, ABq, J 17.7Hz), 3.78 (3H, s), 3.98 (1H, m), 4.88 (1H, d, J 5.0Hz), 4.93-5.04 (2H, m), 5.17 (2H, s), 6.87 (2H, d, J 8.6Hz), 7.32 (2H, d, J 8.6Hz).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[O:15][CH2:14][C@@H:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[CH2:7]1)(=O)C.C[O-].[Na+].Cl.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>CO.O1CCOCC1>[CH3:27][S:28]([O:4][CH2:5][C@@H:6]1[O:15][CH2:14][C@@H:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[CH2:7]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1CN2CCOC[C@H]2CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)OC[C@H]1CN2CCOC[C@H]2CO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate (0.922 g, 4.28 mmol) in methanol (14.0 mL) was added 1.03 mL (4.50 mmol) of sodium methoxide (25% wt. in methanol) dropwise at room temperature. After 5 min., 1.6 mL (6.43 mmol) of 4.0M hydrogen chloride in dioxane was added and a pink precipitate formed. The solution was concentrated in vacuo and the pink solid was taken up in 30.0 mL dichloromethane. This slurry was cooled in an ice bath and triethylamine (3.0 mL, 21.5 mmol) was added, followed by methanesulfonyl chloride (0.37 mL, 4.71 mmol). The resultant yellow solution was stirred for 30 minutes at room temperature. The mixture was then partitioned between dichloromethane and saturated aqueous sodium bicarbonate then the aqueous layer was extracted (3×50 mL dichloromethane). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide crude (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl methanesulfonate which was taken on to the following reaction without purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20](O)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31]>>[CH:14]1([N:10]2[C:8]3[N:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:20]([NH:23][CH2:24][C:25]4[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=4[CH3:31])=[O:21])[C:7]=3[C:12]([CH3:13])=[N:11]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1nn(C2CCCCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 6-cyclopropyl-1-(1-cyclohexyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.501 mmol), and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (123 mg, 0.651 mmol). The product was collected as a solid, 0.190 g (87%). LCMS E-S (M+H)=434.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.07 (m, 4 H), 1.15-1.31 (m, 1 H), 1.36-1.52 (m, 2 H), 1.68 (br. s., 1 H), 1.77-1.99 (m, 6 H), 2.11 (s, 3 H), 2.18-2.29 (m, 4 H), 2.35 (s, 3 H), 4.33 (d, J=4.80 Hz, 2 H), 4.53-4.73 (m, 1 H), 5.87 (s, 1 H), 6.96 (s, 1 H), 8.58 (t, J=4.93 Hz, 1 H), 11.51 (s, 1 H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1
Reactant: Ic1ccc2c(c1)CCCNC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCc2cc(I)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
7-Iodo-2,3,4,5-tetrahydro-1H-2-benzazepine (Preparation 2) (450 mg, 1.648 mmol) was dissolved in DCM (30 ml) and treated with BOC2O (0.459 ml, 1.977 mmol) followed by triethylamine (0.459 ml, 3.30 mmol). The reaction mixture was stirred at RT for 30 minutes. LC/MS showed one major product. The reaction was washed with 0.5M HCl (20 ml), sat NaHCO3 (20 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (650 mg) as a colourless oil. MS (ES) C15H20INO2 requires 373; found 318 (M+H−56)+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][CH2:8][CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[I:7][CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCI
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: ICCOC1CCCCO1
Reaction time: 1 h

Procedure:
Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was added dropwise to a cooled solution of 2-iodoethanol (Aldrich, 98 g, 0.57 mol) in Et2O (1L) containing 0.1 g of p-toluenesulfonic acid (Eastman). The solution was then stirred for 1 h at 5°. Solid K2CO3Mallinckrodt, 5 g) was then added to the reaction mixture and the resulting suspension stirred an additional 1 h at RT. The reaction was then filtered and the remaining solid washed with Et2O (1 L). The organic solutions were combined and concentrated rotary evaporation (in a flask washed with 1% NEt3 in H2O). The crude 2-(2-iodoethoxy)-tetrahydro-2-H-pyran (~100 g, 68.9%) was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C@@H:11]([OH:18])[C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1)([CH3:4])[CH3:3].[H-].[Na+].[Cl:22][C:23]1[C:30]([F:31])=[CH:29][C:26]([C:27]#[N:28])=[C:25](F)[CH:24]=1.O>CN(C)C=O>[Cl:22][C:23]1[C:30]([F:31])=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH:24]=1)[O:18][C@@H:11]([C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1)[CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:19])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: Cn1ccnc1[C@H](O)CCCNC(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1[C@@H](CCCNC(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
The product of step (b) (0.24 g, 0.9 mmol) was dissolved in dry dimethylformamide (20 ml), sodium hydride (60% dispersion in oil, 0.04 g, 0.95 mmol) was added in one portion and the mixture stirred at room temperature for 0.5 h. 4-Chloro-2,5-difluorobenzonitrile (0.16 g, 0.9 mmol), as a solution in dry dimethylformamide (5 ml), was added dropwise and the reaction stirred for 18hat room temperature. Water (25 ml) was added and the reaction mixture extracted with ethyl acetate (3×60 ml). The combined organic extracts were washed with water (2×20 ml), dried (magnesium sulphate) and evaporated. The residue was eluted down a flash chromatography column using hexane:ethyl acetate (1:3) as eluent to give the sub-title compound as a white crystalline solid (0.34 g, 88%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[K+].Cl.[Cl-].[Na+]>C1COCC1>[CH2:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCCO
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: OCCCCOCc1ccccc1
Yield: 97.6 %

Procedure:
In a 2 l flask, a solution of 1,4-butanediol (45 g, 0.5 mol) and benzyl bromide (85.5 g, 0.5 mol) in dry THF (500 ml) is cooled to 0° C. (internal temperature). With vigorous stirring, potassium-tert-butoxide (56 g, 0.5 mol) is added in ~5 g portions, maintaining the internal temperature below 10° C. After addition of 1 N HCl (2 l), the mixture is saturated with sodium chloride, extracted with ether (1.5 l), washed with water, dried, and finally evaporated to give an oil (88 g) which is distilled under vacuum to give the pure title compound (63.5 g), bp0.2 113°-114° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])(C)(C)C.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:7][C@H:8]([C:10]1[CH:11]=[C:12]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: Nc1ccncc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@H](N)c1cccc(Nc2ccncc2)c1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
A mixture of (S)-[1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (3 g), 4-aminopyridine (1.88 g), Pd2(dba)3 (915 mg), di-t-butylbiphenylphosphine (298 mg), K3PO4 (4.24 g) in DME (20 mL) was stirred under reflux for 24 h. The reaction mixture was cooled down to room temperature, diluted with methylene chloride, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography using Biotage eluting with 5% MeOH in ethyl acetate to give the desired product (2.2 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:24]1([C@@H:30]2[CH2:35][NH:34][CH2:33][CH2:32][NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:34]4[CH2:33][CH2:32][NH:31][C@H:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:35]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: c1ccc([C@@H]2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN[C@H](c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 89.6 %

Procedure:
Working under the conditions of Example 20, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (51.6 g) and (R)-2-phenylpiperazine (31.7 g), (R)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (66.86 g) is obtained in the form of a yellow solid, m.p. 221° C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2>C(O)(C)(C)C>[OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH:10]=[CH:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O

Procedure:
19-Hydroxy-4-androstene-3,17-dione and choranil are dissolved in t-butanol and rapidly brought to its reflux temperature. The t-butanol is removed by distillation at atmospheric pressure at such a rate so that the total reflux and distillation time equals one hour. The dark pasty residue is triturated with hot chloroform and cooled. The solid which remains is removed by filtration and the filtrate successively extracted with water, a 2% sodium hydroxide solution and again with water. The organic layer is dried over magnesium sulfate and the solvent removed under vacuum to yield 19-hydroxy-4,6-androstadiene-3,17-dione. The diene so prepared is dissolved in acetone and chilled in an ice bath. Jones reagent is added over a period of about 10 minutes and stirring continued for an additional 45 minutes. The mixture is poured onto water. The solid which forms is filtered and recrystallized from benzene to yield 4,6-androstadiene-3,17,19-trione.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:13]([O:15][C:16]([C:18]1[N:19]([CH3:25])[C:20](Br)=[N:21][C:22]=1[CH3:23])=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[N:19]([CH3:25])[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=2)=[N:21][C:22]=1[CH3:23])=[O:17])[CH3:14]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1cccc(NC(C)=O)c1
Product: CCOC(=O)c1c(C)nc(C#Cc2cccc(NC(C)=O)c2)n1C

Procedure:
The title compound, MS: m/e=326.8 (M+H+), was prepared in accordance with the general method of example 1b from N-(3-ethynyl-phenyl)-acetamide and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.