Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([CH3:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH:6]=[CH:5]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:33])[C:9](=[CH:8][C:7](=[O:32])[CH:6]=[CH:5]2)[C@@H:10]([CH3:31])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)CC(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Analogously to Example 2c, 1.5 g of 11β,21-dihydroxy-17-isovaleryloxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted in 15 ml of pyridine with 7.5 ml of acetic anhydride, worked up, and purified, thus isolating 980 mg of 21-acetoxy-11β-hydroxy-6α-methyl-17-isovaleryloxy-1,4-pregnadiene-3,20-dione, mp 172° C.
Reaction SMILES: [C:1]12([C:9]3[CH:10]=[C:11]([N:19]4[C:23]([NH2:24])=[N:22][C:21]([NH:25][C:26]5[CH:27]=[CH:28][C:29]6[CH2:35][CH2:34][C@H:33]([NH:36]C(OC(C)(C)C)=O)[CH2:32][CH2:31][C:30]=6[CH:44]=5)=[N:20]4)[N:12]=[C:13]4[C:18]=3[NH:17][CH2:16][CH2:15][CH2:14]4)[CH2:8][CH2:7][C:4]([CH:5]=[CH:6]1)=[CH:3][CH2:2]2.Cl.CO.[OH-].[Na+]>O1CCOCC1>[C:1]12([C:9]3[CH:10]=[C:11]([N:19]4[C:23]([NH2:24])=[N:22][C:21]([NH:25][C:26]5[CH:27]=[CH:28][C:29]6[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31][C:30]=6[CH:44]=5)=[N:20]4)[N:12]=[C:13]4[C:18]=3[NH:17][CH2:16][CH2:15][CH2:14]4)[CH2:8][CH2:7][C:4]([CH:3]=[CH:2]1)=[CH:5][CH2:6]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(Nc3nc(N)n(-c4cc(C56C=CC(=CC5)CC6)c5c(n4)CCCN5)n3)cc2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(Nc2ccc3c(c2)CC[C@@H](N)CC3)nn1-c1cc(C23C=CC(=CC2)CC3)c2c(n1)CCCN2
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
(7S)-1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine (23 mg, 0.038 mmol) was added to a 4M solution of HCl in dioxane. In order to improve solubility, 2 mL of MeOH were added which resulted in a clear solution. The reaction mixture was stirred for 6 h at ambient temperature and then neutralized with 2M NaOH which caused the precipitation of the free amine. The product was filtered off, washed with water and dried over night in HV to yield the amino compound, (7S)-1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine (18 mg, 96%). The product was then dissolved in dry DCM. Subsequently, acetaldehyde (˜5 mg, 0.1 mmol) and NaBH(OAc)3 (21 mg, 0.1 mmol) were added. After the mixture was stirred for 2 d at ambient temperature, the solvents were evaporated and the desired product, (7S)-1-(1,4-ethano-8-phenyl-1,2,3,4-tetrahydro-1,5-naphthyridin-6-yl)-N3-(7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, compound #35, was isolated via reverse phase HPLC (10.8 mg, 52% two steps); 1H NMR (DMSO-d6, 300 MHz): 9.04 (s, 1H), 8.69 (s br, 1H), 7.75 (s br, 2H), 7.54-7.66 (m, 5H), 7.41 (d, 1H), 7.26 (s, 1H), 7.01 (d, 1H), 2.87-3.18 (m, 8H), 2.60-2.81 (m, 4H), 2.51-2.55 (m, 2H), 2.00-2.28 (m, 4H), 1.66-1.87 (m, 2H), 1.30-1.56 (m, 2H), 1.12-1.28 (m, 6H) ppm; MS (ES) 549.22 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Sc1ccccc1
Agent: Cl[Sn]Cl
Product: Nc1cc(Br)ccc1Sc1ccccc1
Yield: 99.6 %

Procedure:
The product from Example 121b (2.0 g, 6.45 mmol) was reduced with SnCl2 following the procedure from Example 1f giving the title compound as a clear oil (1.8 g, 100%).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:19][CH2:20][CH2:21][N:22]=2)[CH:15]=[CH:16][CH:17]=1.C[Li].C(=O)=O.CC(C)=O.Cl>O1CCCC1.C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2([CH3:5])[CH2:19][CH2:20][CH2:21][NH:22]2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(C2=NCCC2)c1
Reactant: CCOCC
Agent: Cl
Agent: FB(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1cccc(C2(C)CCCN2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.4 %

Procedure:
Add boron trifluoride diethyl etherate (1.34 g, 9.42 mmol) dropwise over 5 min to a −78° C. solution of 5-(3-methoxy-phenyl)-3,4-dihydro-2H-pyrrole (1.50 g, 8.56 mmol) in tetrahydrofuran (60 mL). After stirring for 45 min, add methyllithium (1.6 M in diethyl ether, 10.70 mL, 17.10 mmol) dropwise over 10 min. After stirring the bright yellow reaction mixture for 2.5 h, warm the reaction mixture slowly to 0° C. After 1.5 h replace the dry ice/acetone cooling bath with an ice bath. After 15 min, quench the reaction using water (50 mL) and saturated aqueous ammonium chloride (50 mL) and adjust the pH to about 11-12 using aqueous 2 M sodium hydroxide. Extract the aqueous layer with 9:1 methylene chloride/chloroform (3×200 mL) and dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain an orange oil. Redissolve the crude oil in methylene chloride (200 mL) and add aqueous 2 M hydrochloric acid (200 mL). Separate the layers and extract the aqueous layer with additional methylene chloride (100 mL) and discard the combined organic layers. Adjust the resulting aqueous layer to a pH of 14 using aqueous 2 M sodium hydroxide (about 250 mL), extract with 1:1 methylene chloride/chloroform (2×250 mL), dry the combined organic layers over magnesium sulfate, filter, and concentrate under reduced pressure to obtain an orange oil (1.30 g). Purify the oil by flash chromatography eluting with a gradient of methylene chloride/90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide (4:1 to 1:1) to obtain the title compound (650 mg, 40%) as a light yellow oil. MS (APCI+): 192 [Cl2H17NO+H]+; 1H NMR (300 MHz, CDCl3): δ 7.24 (symmetrical m, 1H), 7.09-7.03 (m, 2H), 6.75 (ddd, J=8.1, 2.6, 0.9 Hz, 1H), 3.81 (s, 3H), 3.16-2.94 (symmetrical m, 2H), 2.14-2.01 (m, 1H), 1.94-1.67 (m, 4H), 1.42 (s, 3H).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([NH:10][C:11]3[C:15]([CH3:16])=[CH:14][S:13][CH:12]=3)[NH:9][C:5]=2[CH:4]=1.[Br:19]N1C(=O)CCC1=O>C(O)(=O)C>[ClH:1].[Br:19][C:12]1[S:13][CH:14]=[C:15]([CH3:16])[C:11]=1[NH:10][C:8]1[NH:7][C:6]2[CH:17]=[CH:18][C:3]([F:2])=[CH:4][C:5]=2[N:9]=1
Reactant: Cc1cscc1Nc1nc2ccc(F)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC(=O)O
Product: Cc1csc(Br)c1Nc1nc2cc(F)ccc2[nH]1
Reaction time: 0.17 h

Procedure:
(5-Fluoro-1H-benzimidazol-2-yl)-(4-methylthiophene-3-yl)amine (300 mg) (example 1) was dissolved in glacial acetic acid (50 ml). At room temperature, N-bromosuccinimide (207 mg) dissolved in glacial acetic acid (10 ml), was slowly added dropwise, with vigorous stirring. After the addition had ended, stirring was continued for another 10 min and the glacial acetic acid was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated potassium carbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. Following removal of the solvent under reduced pressure, water and 2N hydrochloric acid were added to the residue and the mixture was freeze-dried. This gave 245 mg of the desired product.
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:43])[N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]3)[CH3:31])[CH:23]=2)=[CH:19][CH:18]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1>C(O)C>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]([CH3:31])[C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]4[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=4)=[S:58])=[CH:45][CH:44]=3)[CH:27]=[CH:26][N:25]=2)=[O:43])[CH2:33][CH2:34]1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (119 mg) to a solution of 3-[4-(4-aminophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (121 mg) in ethanol (2.0 ml), the mixture was stirred for 10 minutes at room temperature. Next, 2-(4-fluorophenyl)acetyl isothiocyanate (2.34 ml, 0.25 M solution in toluene) was added thereto and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were combined and concentrated. The residue was purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were concentrated, and saturated aqueous sodium hydrogencarbonate was added to the resultant residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated to provide the title compound (26.3 mg, 14.8%) as white powder.
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:11][C:12]1[C:17]([F:18])=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[C:15]([NH2:28])=[C:14]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:13]=1>>[CH2:1]([C:4]1([S:7]([NH:28][C:15]2[C:14]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:13][C:12]([F:11])=[C:17]([F:18])[C:16]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: COCCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Product: C=CCC1(S(=O)(=O)Nc2c(OCCOC)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Yield: 15.8 %

Procedure:
According to the general procedure B, 1-allyl-cyclopropanesulfonyl chloride (450 rug, 2.5 mmol) was reacted with 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-(2-methoxyethoxy)benzene-1,2-diamine (219 mg, 2.5 mmol) to obtain the title product (230 mg, 78%); m/z=581 [M−1].
Reaction SMILES: CC(C)(C)C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.C[O-].[Na+]>CO>[CH3:29][S:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[NH:5][N:6]=[CH:7]4)[CH2:16]2)=[CH:27][CH:26]=1
Reactant: CSc1ccc(CN2CCCC(Nc3ccc4c(cnn4C(=O)C(C)(C)C)c3)C2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(CN2CCCC(Nc3ccc4[nH]ncc4c3)C2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
Into a 25 mL round bottom flask were added 2,2-dimethyl-1-(5-(1-(4-(methylthio)benzyl)piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one (250 mg, 0.6 mmol), methanol (5 mL), and sodium methoxide (93 mg, 1.7 mmol). The reaction was stirred at room temperature until the starting material was consumed as monitored by HPLC. The mixture was diluted with ethyl acetate (10 mL), washed with water (2×10 mL), and the organic phase was separated, dried over MgSO4, filtered and evaporated to dryness to afford the title compound (180 mg, 89%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:9][C@H:8]1[N:21]1[C:40]2[N:39]=[C:28]([NH:29][CH2:30]SC3C=CC(C)=CC=3)[NH:27][C:25](=[O:26])[C:24]=2[N:23]=[CH:22]1)(=[O:5])[CH3:4].P([O-])(O)(O)=O.[K+].C(Cl)Cl>CS(C)=O.CO>[C:3]([O:6][C@@H:7]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:9][C@H:8]1[N:21]1[C:40]2[N:39]=[C:28]([NH:29][CH3:30])[NH:27][C:25](=[O:26])[C:24]=2[N:23]=[CH:22]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NCSc4ccc(C)cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CNc1nc2c(ncn2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Temperature: 100 °C
Yield: 75 %

Procedure:
Sodium borohydride (625 mg, 16.5 mmol, 1.82 eq) was added to a solution of 2′,3′,5′-tri-O-acetyl-2-N-(p-methylphenylthiomethyl)guanosine 2 (5.0 g, 9.2 mmol, 1.0 eq) in dimethyl sulfoxide (25 mL). The mixture was heated at 100° C. for 1 h and then cooled to room temperature. Reaction products were neutralized with 1 M aqueous potassium dihydrogen phosphate solution. The precipitate obtained was collected by filtration and further washed with acetone. The residue was chromatographed on a column of silica gel to give 3 in 75% yield (2.93 g, 6.93 mmol). TLC (CH2Cl2:MeOH, 9:1 v/v): Rf=0.45; 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 1.92 (s, 3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.8 (d, J=4 Hz, 3H), 4.11-4.15 (dd, J=6, 11.6 Hz, 1H), 4.23-4.25 (m, 1H), 4.33-4.37 (dd, J=4, 11.6 Hz, 1H), 5.7 (t, 1H), 5.8 (t, 1H), 5.9 (d, J=4 Hz, 1H), 6.4 (q, 1H), 7.79 (s, 1H), 10.79 (s, 1H); 13C NMR (DMSO-d6, 400 MHz) δ (ppm): 20.2, 20.3, 27.7, 40.4, 62.7, 69.7, 72.1, 78.5, 86.4, 117.3, 136.9, 150.2, 153.3, 156.6, 169.3, 169.4, 169.9; ESI-MS (ES+) calculated for C17H21N5O8 423.139, found 424.2 (M+H+), 446.2 (M+Na+), 847.3 (M+H+), 869.3 (2M+Na+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([CH:30]5[CH2:31][CH2:32][O:28][CH2:29]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCOC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CCOC1

Procedure:
The title compound, white solid (101 mg, 79%), MS (ISP) m/z=429.3 [(M+H)+], mp 208.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-Dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and rac-tetrahydrofuran-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].F[C:21]1[CH:22]=[N+:23]([O-:30])[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:21]2[CH:22]=[N+:23]([O-:30])[CH:24]=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)c2ccccc12
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2c[n+]([O-])ccc2[N+](=O)[O-])c2ccccc12
Reaction time: 0.25 h

Procedure:
To a solution of 4-methoxy-1-naphthol (8.87 g) in 50 ml of DMF was added sodium carbonate (7.8 g) portionwise, and after the addition was complete the mixture was stirred for 15 minutes. Then a solution of 3-fluoro-4-nitropyridine-N-oxide (8.0 g) in 50 ml DMF was added dropwise at room temperature. The reaction was then allowed to proceed for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with NaCl (sat) and dried (anhy. MgSO4).
Reaction SMILES: [I:1][C:2]1[N:3]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=[C:5]([C:7](O)=[O:8])[N:6]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[NH2:48][C@H:49]([C:56]([O:58][CH3:59])=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53]>O1CCCC1>[I:1][C:2]1[N:3]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=[C:5]([C:7]([NH:48][C@H:49]([C:56]([O:58][CH3:59])=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:8])[N:6]=1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1)C(=O)OC
Yield: 75.3 %

Procedure:
2-Iodo-1-triphenylmethylimidazole-4-carboxylic acid (1.443 g, 3.0 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (553 mg, 3.15 mmol), 4-methylmorpholine (0.614 mL, 6.6 mmol), dimethyl L-glutamate hydrochloride (698 mg, 3.3 mmol), and tetrahydrofuran (20 mL) were then allowed to react in the manner described in Example 15 to yield dimethyl N-(2-iodo-1-triphenylmethylimidazol-4-ylcarbonyl)--L-glutamate (1.44 g, 75%, mp 86-88° C.): 1H N (CDCl3) δ 7.47 (s, 1H), 7.44 (d, 1H, J=8.6 Hz), 7.32-7.26 (m, 9H), 7.21-7.05 (m, 6H), 4.72 (m, 1H), 3.71 (s, 3H), 3.62 (s, 3H), 2.41 (m, 2H), 2.27 (m, 1H), 1,99 (m, 1H). HRMS calcd for C30H28IN3O5 637.1074, found 637.1054. Anal. Calcd for C30H28IN3O5 : C, 56.52; H, 4.43; N, 6.59. Found: C, 56.36; H, 4.45, N, 6.57.
Reaction SMILES: [CH3:1][S:2]([C:5]#[C:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:4])=[O:3]>ClC1C=CC=CC=1Cl>[CH3:1][S:2]([C:5]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:10]2[CH2:9][CH2:8][CH2:7][C:6]=12)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)C#CCCC/C=C/c1ccccc1
Solvent: Clc1ccccc1Cl
Product: CS(=O)(=O)c1c2c(cc3ccccc13)CCC2
Temperature: 225 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added enyne 5f (0.050 g, 0.20 mmol) in o-dichlorobenzene (2.3 mL). The reaction was irradiated with stirring at 225° C. for 20 min until complete by TLC. The reaction turned golden in color. The crude product was purified by silica gel column chromatography (14 g silica cartridge, 0-15% ethyl acetate/hexanes) to yield naphthalene 6f as a colorless oil (0.038 g, 78%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([CH:24]5[CH2:25][CH2:26][N:27]([C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[CH2:28][CH2:29]5)=[O:36])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)CO)CC3)ccc1OCC2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)(C)CO)CC3)ccc1OCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol from Example 1 (229 mg, 0.474 mmol) in DCM (10 mL) was added TFA (110 μL, 1.42 mmol) followed by a solution of m-CPBA (82 mg, 0.474 mmol) in DCM (2 mL). The resulting mixture was stirred for 1 h at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-35% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH affording 186 as a white solid (177 mg, 75%). LCMS: RT 2.45 min [M+H]+ 499.2. 1H NMR (DMSO, 400 MHz): δ 8.59 (1H, d, J=2.26 Hz), 7.97 (1H, s), 7.93 (1H, s), 7.53 (1H, dd, J=8.53, 2.28 Hz), 7.25 (1H, d, J=8.53 Hz), 5.80-5.67 (1H, m), 4.61-4.43 (4H, m), 4.22-4.16 (1H, m), 3.21 (2H, d, J=4.59 Hz), 3.06-2.96 (2H, m), 2.73-2.63 (1H, m), 2.17-2.05 (2H, m), 1.77 (1H, bd, J=12.25 Hz), 1.59 (1H, bd, J=12.59 Hz), 1.52-1.34 (8H, m), 0.88 (6H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[N:6][CH:7]=1.[OH:11]S(O)(=O)=O>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH2:10])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1cncc(Br)c1
Solvent: CCO
Solvent: O
Product: NC(=O)Cc1cncc(Br)c1
Temperature: 110 °C

Procedure:
(5-Bromo-pyridin-3-yl)-acetonitrile (1 g, 5.1 mmol) was dissolved in a mixture of EtOH (20 ml) and water (1.2 ml). H2SO4 (6.8 ml) was then added to the mixture and the mixture was heated at ˜110° C. for 24 hrs. Solvent was removed under vacuo, taken up in EtOAc and washed with 2N Na2CO3 solution. Drying and evaporation gave a crude oil which was sufficiently pure for the next step. Alternatively, the above crude was dissolved in 7N NH3— MeOH (20 ml) and stirred at R.T over the weekend. Solvent was evaporated and purified by flash column eluting with DCM-MeOH (95:5) to obtain a yellow colored material (0.9 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[N:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][NH2:14])=O)=[C:4]([CH3:19])[CH:3]=1.I.CS[CH:23]([NH2:25])[NH2:24].O>N1C=CC=CC=1>[NH2:25][C:23]1[NH:24][C:11]([C:10]2[CH:15]=[CH:16][N:17]=[CH:18][C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[CH3:19])=[N:13][N:14]=1
Reactant: CSC(N)N
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)NN
Agent: I
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(I)ccc1Nc1cnccc1-c1nnc(N)[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
A reaction mixture of 3-(4-Iodo-2-methyl-phenylamino)-isonicotinic acid hydrazide (120 mg, 0.33 mmol, 1 eq) and C-Methylsulfanyl-methanediamine hydroiodide (104 mg, 0.47 mL, 1.45 eq) in pyridine (2 mL) in sealed tube was heated to 140° C. while stirring for 4 hrs. After cooling, it was poured into water, extracted with EtOAc, and the combined organic fractions, dried over anhydrous MgSO4. After filtration and solvent removal the remaining crude product was subjected to silica gel column chromatography (eluent:Hexane EtOAc=1:1) to afford the desired product (35 mg). [4.26 min; 393(M+1)]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]([CH3:14])[CH2:12][C:11]([OH:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1CC(O)=NN1c1ccc(Cl)c(Cl)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCOCC2)nn1-c1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A mixture of (VI) (300 mg, 1.23 mmol), N-(2-chloroethyl)morpholine hydrochloride (230 mg, 123 mmol), K2CO3 (341 mg, 2.47 mmol), and NaI (185 mg, 1.23 mmol) in dry dimethyl formamide (5 ml) was stirred overnight at 70° C. The mixture was poured into water (20 ml), extracted four times with Et2O, and the organic extracts were washed with saturated NaCl solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified via MPLC (light petroleum/AcOEt 4:1) to yield (VII) (303 mg, 69%) as a colorless oil. TLC CHCl3/MeOH 9:1.