Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])[O:29][C:30](Cl)(Cl)Cl)Cl.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:29][CH2:30][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[O:37][CH3:36]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: COc1ccccc1CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Yield: 105.7 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methoxyphenyl)methanol (32 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (79 mg, yield 93%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:18][O:19][CH3:20]
Reactant: COc1ccc(C=O)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(C=O)ccc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of isovanillin (5.00 g, 32.9 mmol) in N,N-dimethylformamide (300 ml) were added potassium carbonate (5.00 g, 36.1 mmol) and chloromethyl methyl ether (2.91 g, 36.1 mmol), and the mixture was stirred for 4 hours at 50° C. The mixture was allowed to cool to room temperature, followed by addition of water. The mixture was extracted with ethyl acetate-toluene (3:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=3:1) to give the subject compound (5.80 g, 89.9%).
Reaction SMILES: ClCC(C)(C1C=CC=CC=1)C.[CH3:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH3:24])([CH3:23])[CH2:15][NH:14]1.C1C2C(=CC=CC=2)C=CN=1.[Cl:35][CH:36]([Cl:40])[C:37](Cl)=[O:38].[OH-].[Na+]>C(Cl)Cl.C(#N)C>[Cl:35][CH:36]([Cl:40])[C:37]([N:14]1[CH2:15][C:16]([CH3:23])([CH3:24])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]1[CH3:12])=[O:38]
Reactant: CC1NCC(C)(C)c2ccccc21
Reactant: O=C(Cl)C(Cl)Cl
Agent: CC(C)(CCl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccc2cnccc2c1
Product: CC1c2ccccc2C(C)(C)CN1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1 (Method B), 1-chloro-2-methyl-2-phenyl-propane and acetonitrile were converted to 1-methyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 4.0 g of this isoquinoline compound and 50 ml methylene chloride. With this mixture stirred, 2 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 20 minutes and then made alkaline with aqueous sodium hydroxide. The organic extract was dried with magnesium sulfate and stripped of solvent. The residue was recrystallized from ethanol to provide 4.2 g of a white cubic-crystal product having the elemental analysis reported in Table I.
Reaction SMILES: CS(C1C=CC(C2N3C(C=NC(NC4C=CC(N5CCOCC5)=CC=4)=N3)=C(C)C=2)=CC=1)(=O)=O.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][CH2:44][CH:43]([C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[O:48])[CH2:42]2)=[CH:37][CH:36]=1.[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59].[CH3:63][O:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]1[N:79]2[C:74]([CH:75]=[N:76][C:77](NC3C=NC(N4CCOCC4)=CC=3)=[N:78]2)=[CH:73][CH:72]=1.COCC(O)C>CN1CCCC1=O>[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59].[CH3:63][O:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]1[N:79]2[C:74]([CH:75]=[N:76][C:77]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:46][CH2:45][CH2:44][CH:43]([C:47]([N:49]5[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]5)=[O:48])[CH2:42]4)=[CH:37][CH:36]=3)=[N:78]2)=[CH:73][CH:72]=1
Reactant: CN1CCN(C(=O)C2CCCN(c3ccc(N)cc3)C2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)nc3)nn12
Agent: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n2nc(Nc3ccc(N4CCOCC4)cc3)ncc12
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCCC(C(=O)N5CCN(C)CC5)C4)cc3)nn12

Procedure:
The titled compound (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid was prepared in an analogous fashion to [7-(4-Methanesulfonyl-phenyl)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine of Example 107 after: replacing 4-(4-morpholino)aniline with [1-(4-Amino-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone, replacing 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine with 2-Methanesulfinyl-7-(2-methoxy-phenyl)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (of Example 47), and replacing the solvent N-Methylpyrrolidinone with 1-Methoxy-2-propanol, to give after purification via reverse phase HPLC (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid as a brown lyophylate (29 mg, 22%). LC/MS (E/I+) 526.22 (M+H). NMR 1H (DMSO-d6)-10.01 (bs, 1H), 9.45 (bs, 1H), 8.96 (s, 1H), 7.81-7.79 (m, 1H), 7.72-7.69 (d, 2H, J=8.58 Hz), 7.50-7.46 (m, 1H), 7.23-7.11 (m, 4H), 6.96-6.93 (m, 2H), 4.46-4.19 (bm, TFA salt and water provided poor resolution), 3.81 (s, 3H), 3.58-2.93 (bm; smeared as TFA salt), 2.83 (s, 3H), 1.86 (bs, 3H), 1.75 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:24]([C:27]1[N:31]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:30]=[C:29]([CH:36]=O)[CH:28]=1)[CH2:25][CH3:26]>>[C:32]([N:31]1[C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][C:29]([CH2:36][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)=[N:30]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Product: CCCc1cc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nn1C(C)(C)C
Yield: 86 %

Procedure:
Compound 93 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[CH:20]=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:24])N.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+]>O1CCOCC1.O>[C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20]([OH:24])=[O:21])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a suspension of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline-3-carbaldehyde G1 (0.55 mmol) in dioxane (6.8 mL) and water (2.4 mL), sulfamic acid (0.9 mmol) and sodium dihydrogen phosphate (2.33 mmol) were added. The mixture was cooled to 0° C. and sodium chlorite (0.95 mmol, dissolved in the minimum amount of water) was added. Other two additions of an equal amount of oxidant were made during 24 h of stirring, then the reaction was filtered and the solid product was washed with water and dried, resulting in 94% yield of the title compound. ESI (+) MS: m/z 289 (MH+); MS (ES−) 287. 1H NMR: 7.35-7.41 (m, 1H), 7.45-7.56 (m, 4H), 7.96 (d, J=9.00, 1H), 8.58 (d, J=9.00, 1H), 8.68 (d, J=5.17, 1H), 8.78 (d, J=5.17, 1H), 9.57 (s, 1H), 11.47 (bs, 1H), 13.54 (bs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH2:17][N:18]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[C:19]2=O)=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH2:17][N:18]2[CH2:19][C:20]3[C:25](=[CH:24][C:23]([CH3:27])=[C:22]([CH3:28])[CH:21]=3)[CH2:26]2)=[CH:5][CH:6]=1
Reactant: Cc1cc2c(cc1C)C(=O)N(CCC1CCCCN1CCCc1ccncc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2c(cc1C)CN(CCC1CCCCN1CCCc1ccncc1)C2

Procedure:
Prepared from 2-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid-2-yl)-ethyl]-5,6-dimethyl-1-oxo-1,3-dihydro-isoindole and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][C:14]2=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([C:22]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])=[CH:6][CH:5]=[CH:4][N:3]2[CH:21]=1)=[O:24])[CH3:27]
Reactant: Nc1ncccc1OCCCCN1C(=O)CSC1=O
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2cccc(OCCCCN3C(=O)CSC3=O)c2n1

Procedure:
Using 5.69 g (20 mmol) of 3-[4-(2-aminopyridin-3-yloxy)butyl]thiazolidine-2,4-dione and 2.51 ml (20 mmol) of ethyl bromopyruvate, the same procedure as in Reference Example 27 was followed, to yield 3.28 g (43.5%, light orange oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>C(#N)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[N:7]=[C:6]2[N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1n[nH]c2nc(F)ccc12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2nc(F)ccc12
Reaction time: 1 h

Procedure:
A stirred solution of 6.67 g (44.2 mmol) of 6-fluoro-3-methyl-1H-pyrazolo[3,4-b]pyridine in 100 mL of acetonitrile under nitrogen was treated with 5.40 g (44.2 mmol) of DMAP and 6.46 mL (46.4 mmol) of triethylamine. A solution of 11.56 g (53.0 mmol) of (BOC)2O in 20 mL acetonitrile was added dropwise via a cannula and the resulting reaction mixture stirred for 1 hour until completion as determined by LC/MS analysis. The reaction was quenched with brine and extracted with EtOAc (3×). The combined organic layers were washed with H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified via silica gel chromatography (0-70% EtOAc/hexane) to yield the title compound. 1H NMR (CDCl3): 1.74 (s, 9H), 2.60 (s, 3H), 6.95 (d, 1H), 8.08 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH:16](=[O:18])[CH3:17].O>C1COCC1>[Cl:1][C:2]1[C:7]([CH:16]([OH:18])[CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC=O
Reactant: Clc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cccnc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
A solution of 2-chloropyridine (I) (9.39 mL, 0.1 mol) in anhydrous THF (50 mL) was added slowly to a solution of LDA (2.0 M solution in THF/hexane/ethylbenzene, 50 mL, 0.1 mol) in THF (200 mL) stirred at −78° C. under nitrogen. The stirring was continued at −78° C. for an additional 3 h before adding acetaldehyde (6.17 mL, 0.110 mol). The solution was stirred at −78° C. for another 2 h before allowing the temperature to rise to −40° C. A solution of water (4 mL) in THF (40 mL) was added slowly to the solution. When the temperature reached −10° C., additional water (200 mL) was added to the solution. The solution was extracted with ethyl ether (3×100 mL) The combined organic phase was dried over MgSO4, filtered and evaporated under reduced pressure to get a brown viscous residue. The crude product was purified on a flash silica gel column (1:1 DCM:hexane→100% DCM) to produce 1-(2-chloropyridin-3-yl)ethanol (II) as a brown viscous oil (6 g, 38.1 mmol, 38% yield). 1H NMR (CDCl3) δ ppm 1.52 (d, J=6.41 Hz, 3H), 2.51 (bs, 1H), 5.24 (m, 1H), 7.28 (m, 1H), 7.97 (dd, J=7.72, 1.70, 1H), 8.27 (dd, J=7.72, 1.79, 1 H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)[CH2:5]1)[CH2:2][CH3:3].N1C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CC[O-].[Na+]>C(Cl)Cl.CCO>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:15][C:12]2[CH:11]=[N:10][C:9]([CH:6]3[CH2:7][CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]3)=[N:14][CH:13]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCCN1CCC(c2ncc(N)cn2)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCN1CCC(c2ncc(NS(=O)(=O)c3ccc(Br)cc3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
The crude 2-(1-propyl-pyrrolidin-3-yl)-pyrimidin-5-ylamine (about 1.11 mmol) was dissolved in CH2Cl2:pyridine, 9:1 (50 ml) and 4-bromobenzensulfonyl chloride (566 mg, 2.21 mmol) was added. After stirring at room temperature overnight, the reaction mixture was filtered and concentrated. The raw material was then dissolved in a solution of EtONa (400 mg, 5.87 mmol) in EtOH (35 ml) and the resulting solution was heated under reflux for 1 h. Silica gel (1 g) was next added to the mixture and the solvent removed under reduced pressure. Following flash column chromatography (CH2Cl2:methanol, 9:1) provides the title compound (100 mg, 21% for four steps) as a yellow gum.
Reaction SMILES: O1[C@H]2C[C@H:5]3[C@:20](C)([CH2:21][C@@H]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.Cl(O)(=O)(=O)=[O:26].[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O>[OH:30][C@H:34]1[CH2:21][C@@:20]2([CH3:5])[C@@H:31]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:32][C@@H:33]1[OH:26]
Reactant: C1CCOC1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 0.25 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (207 mg.) in hot tetrahydrofuran (6 ml.) was treated with perchloric acid (60%, 0.05 ml.) in tetrahydrofuran (2 ml.) and water (2 ml.). The reaction mixture was concentrated to 5 ml., allowed to stand for 15 minutes and boiled for 30 minutes with the concurrent addition of water. The mixture was poured into ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, dried over sodium sulphate and evaporated to a crystalline mass which was purified by preparative TLC to give the title compound (70 mg.) as colourless crystals, m.p. 194°-198°, [α]D + 103.5°.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:39][S:40]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:42])=[O:41])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.Cl.[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH2:83])=[O:81]>>[O:74]=[C:71]1[CH:72]=[CH:73][C:69](=[O:68])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH:83][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:39][S:40]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)(=[O:42])=[O:41])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:81]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: Cl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
7.4 mg (7.9 mmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylsulphonyl)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and 6.2 mg (23.5 mmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride were coupled and worked up in analogy to Intermediate 157. 6.9 mg (74% of theory) of the title compound were obtained as a solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]1[CH2:13][C:14]([O:16]C)=[O:15]>C(O)(=O)C>[O:2]=[C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CN1C(=O)CCc2cnccc21
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)CCc2cnccc21
Temperature: 60 °C

Procedure:
Aqueous 1N HCl (2 mL) was added to a solution of methyl 2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetate (1.24 g, 5.67 mmol) in acetic acid (5 mL) and the resulting mixture was heated to 60° C. for 4 h. The solution was concentrated under vacuum to give 2-(2-Oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid. Retention time (min)=0.275, method [1], MS(ESI) 207.0 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2ccccc2)cc1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 5.72 g (25.0 mmol, 1.0 eq.) of methyl 4-bromomethylbenzoate (Aldrich) and 3.80 g (27.5 mmol, 1.1 eq.) of K2CO3 in 10 mL of DMF at ambient temperature was added a solution of 2.59 g (27.5 mmol, 1.1 eq.) of phenol in 10 mL of DMF dropwise and the mixture stirred overnight. The reaction mixture was poured into 100 mL of water and extracted with 3×100 mL portions of 25% CH2Cl2 -hexanes. The combined organic phases were extracted with 3×100 mL portions of water, dried (MgSO4), filtered and concentrated in vacuo. The solid residue was recrystallized from ~50 mL of hexanes to give 5.31 g (88%) of the title compound as a white, crystalline solid. 1H NMR (300 MHz, CDCl3) δ8.05 (d, 2H), 7.51 (d, 2H), 7.26-7.33 (m, 2H), 6.95-7.02 (m, 3H), 5.13 (s, 2H), 3.92 (s, 3H). MS (DCl) m/e 260 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:18])[CH:5]=[CH:4][C:3]=1[C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27].CCN=C=NCCCN(C)C.[CH3:40][C:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH3:43])[NH2:42]>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:42][C:41]([CH3:43])([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH3:40])=[O:16])=[CH:10][CH:9]=2)[C:6](=[O:18])[CH:5]=[CH:4][C:3]=1[C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]
Reactant: Nc1c(C(=O)c2ccc(F)cc2F)ccc(=O)n1-c1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)Cc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of {4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenyl}acetic acid (Intermediate 5) (0.13 g, 0.34 mmol) in DCM/DMF (1:1, 6 ml) were added EDCI (0.07 g, 0.36 mmol), DMAP (0.004 g, 0.03 mmol) followed by the addition of tert-butyl 2-methylalaninate (Intermediate 8) (0.057 g, 0.36 mmol). The mixture was stirred at RT for overnight. The reaction mixture was diluted with EtOAc (20 ml), washed with water (2×20 ml), brine (20 ml), dried (MgSO4), filtered and concentrated under reduced pressure to leave a yellow oil. Purification by column chromatography (100% EtOAc) afforded the title compound as an off-white solid (78 mg, 44% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:20].Cl.[NH2:22][CH2:23][CH2:24][O:25][NH2:26].N1C=CC=CC=1.C(O)C>[OH-].[Na+].C(OCC)(=O)C>[ClH:20].[ClH:20].[NH2:22][CH2:23][CH2:24][O:25][N:26]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reactant: NCCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: NCCON=C(CCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A mixture of 3-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-propanone (4.65 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (3.10 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was diluted with 10% sodium hydroxide solution and ethyl acetate. The layers were separated. The aqueous phase was extracted with ethyl acetate, the organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was flash it chromatographed (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added to the solution. The solid was collected and recrystallized twice from absolute ethanol/ether to give 2.8 g (40%) of product, mp 213°-214° C. (dec).