Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 46.8 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1S,3R)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 8, 0.250 g, 0.385 mmol) 2,2-Dimethylsuccinic anhydride (0.26 ml, 2.31 mmol) and DMAP (0.094 g, 0.77 mmol) in pyridine (10 ml) were added at room temperature then the reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with EtOAc, the organic layer was washed with water, 1N HCl, water, brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford the title compound as a off white solid. Wt: 0.140 g: Yield: 46.8%; 1H NMR. (300 MHz, CDCl3): δ 5.95 (d, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.52-4.43 (m, 1H), 4.19-4.09 (m, 1H), 3.82-3.40 (m, 8H), 3.17-3.04 (m, 1H), 2.92-1.82 (m, 1H), 2.71-2.29 (m, 6H), 2.00-1.91 (m, 3H), 1.80-1.09 (m, 28H), 1.00-0.77 (m, 21H); Mass: [M+1]+ 779 (100%), [M+Na]+ 801 (15%); IR (KBr, cm−1): 3419, 2952, 2867, 1757, 1733, 1729, 1638, 1631, 1460, 1452, 1376, 1243, 1180, 1117, 1067, 978, 879, 775; M.R: 248.7° C.-252.6° C.; HPLC: 87.7%
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7](=[O:27])[CH:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: COc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
(Z)-7-Chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (128 mg, 0.235 mmol) was dissolved in anisole (1 mL) under nitrogen and AlCl3 (125 mg, 0.939 mmol) was added in one portion. The resulting orange solution was heated to 85° C. for 2 h. After the mixture was cooled to room temperature, ice and ethyl acetate were added and the mixture was stirred for 30 min. The layers were partitioned and the organic layer was washed with water then brine. The combined aqueous layers were back-extracted with ethyl acetate and the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel, eluting with 5%, then 30% ethyl acetate in hexanes to give (Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one as a white solid (99 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 3.60-3.77 (m, 2H), 3.84 (s, 3H), 3.84-3.86 (m, 1H), 6.88 (dd, J=7, 2 Hz, 2H), 7.08 (d, J=9 Hz, 1H), 7.15-7.33 (m, 3H), 7.38 (dd, J=7, 2 Hz, 2H), 7.45 (dd, J=9, 2 Hz, 1H), 7.60 (dd, J=8, 2 Hz, 1H), 8.59 (s, 1H); ESI m/z 425.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([OH:19])=O)[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:19])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C[C@H]2CCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(C[C@H]2CCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
585 mg (purity 73%, 1.1 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoic acid (mixture of enantiomerically pure diastereomers 1 and 2) and 225 mg (1.2 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 327 mg (53% of theory)
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][OH:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO.Cl>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:51])([CH3:52])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][OH:43])[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][OH:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1CO
Agent: Cl
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO)cc1-c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-{6-[(7S ,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H) -yl]-4-[2-(hydroxymethyl)phenyl]-3-pyridinyl}-N ,2-dimethylpropanamide (D61, 24.6 mg, 0.0315 mmol) was suspended in dry MeOH (1 mL) before adding c.HCl solution (5 drops). The reaction mixture was then stirred at R.T. for 3 hours. Poured directly onto a 5 g SCX column, washing with MeOH (2×10 mL) before eluting the compound off with NH3 in MeOH (4×10 mL). Solvent evaporated. Residue purified on a 5 g sek pak column eluting with 0-100% EtOAc/Pent followed by 0-10% MeOH/EtOAc. Solvent evaporated to afford the title compound as a colourless gum.
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].Cl.Cl.[CH2:11]([NH:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>C(O)(=O)C>[CH2:11]([N:18]1[C:5](=[O:6])[CH:4]=[C:2]([CH3:3])[C:1](=[O:8])[NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNCc1ccccc1
Reactant: CC1=CC(=O)OC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cc(=O)n(Cc2ccccc2)[nH]c1=O

Procedure:
A slurry of citraconic anhydride (5.61 g, 50.0 mmol), benzylhydrazine dihydrochloride (9.80 g, 50.0 mmol) and potassium acetate (9.80 g, 100 mmol) in acetic acid (100 mL) was heated to reflux for 17 h. The reaction mixture was cooled and filtered. The filtrate was evaporated under reduced pressure and re-evaporated from toluene. The gummy yellow residue was partitioned between sodium carbonate solution (90 mL, 4 N) and EtOAc (50 mL). The aqueous extract was washed once with EtOAc and then slowly added to hydrochloric acid (3 M, 140 mL). The resulting white precipitate was collected, washed with water and dissolved in chloroform (1 L). The insoluble material was collected and boiled in EtOAc and filtered hot, to give 1,2-dihydro-1-benzyl-4-methyl-3,6-pyridazinedione as a white solid, mp >200° C. (1.85 g, 17%). Part IA compound.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]2>>[F:33][C:30]1[CH:31]=[CH:32][C:23]([N:22]=[CH:11][C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:20][CH3:21])[CH2:18][CH3:19])=[C:24]2[C:29]=1[NH:28][C:27](=[O:34])[CH:26]=[CH:25]2
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Reactant: CCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Product: CCC(CC(O)(C=Nc1ccc(F)c2[nH]c(=O)ccc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 29, 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 5-amino-8-fluoroquinolin-2(1H)-one are condensed to give 8-fluoro-5-{[4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. Reaction with 1 M boron tribromide solution after column chromatography on silica gel (hexane/ethyl acetate 33-100%) and preparative HPLC yield not only the desired product but also the methyl ether cleaved compounds Example 35 and 44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[S:46]1[CH2:51][CH2:50][CH:49](O)[CH2:48][CH2:47]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:36][C:29]1[CH:30]=[C:31]([O:35][CH:49]2[CH2:50][CH2:51][S:46][CH2:47][CH2:48]2)[CH:32]=[C:33]([CH3:34])[C:28]=1[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=2)[CH:23]=1
Reactant: OC1CCSCC1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCSCC2)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (3.0 g, 4.73 mmol), tetrahydro-2H-thiopyran-4-ol (0.62 g, 5.20 mmol) and triphenylphosphine (1.36 g, 5.20 mmol) in tetrahydrofuran (60 mL) was added diethyl azodicarboxylate (40% toluene solution, 2.79 mL, 6.15 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. To the reaction mixture were added reagents (tetrahydro-2H-thiopyran-4-ol, triphenylphosphine and diethyl azodicarboxylate) in a half amount as mentioned above, and the mixture was further stirred for 8 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (3.5 g, yield 100%) as a pale-yellow oil.
Reaction SMILES: [C:1]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(O)[C:28]2[C:19](=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(O)[C:17]2[C:8]1=[CH:9][C:10]1[C:15]([CH:16]=2)=[C:14]2[CH:42]=[CH:43][CH:44]=[CH:45][C:13]2=[CH:12][CH:11]=1.I.C(=O)([O-])O.[Na+]>C(OC(C)C)(C)C.ClCCl>[C:1]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[C:17]([C:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[C:19]3[C:28]=1[CH:27]=[C:26]1[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]1)=[CH:20]3)=[CH:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]3[CH:45]=[CH:44][CH:43]=[CH:42][C:14]3=1)[CH:9]=2
Reactant: OC1(c2ccccc2-c2ccccc2)c2cc3ccccc3cc2C(O)(c2ccccc2-c2ccccc2)c2cc3c(ccc4ccccc43)cc21
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: c1ccc(-c2ccccc2-c2c3cc4ccccc4cc3c(-c3ccccc3-c3ccccc3)c3cc4c(ccc5ccccc54)cc23)cc1
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
In 150 ml of isopropyl ether and 75 ml of dichloromethane, 1.5 g (2.3 mmole) of 8,15-bis(p-biphenylyl)-8,15-dihydro-8,15-dihydroxybenzo[a]-pentacene was suspended. To the obtained suspension, 40 ml of a 57% aqueous solution of hydrogen iodide was added under the refluxing condition and the obtained mixture was stirred for 5 minutes. After the reaction was completed, the reaction solution was added to 500 ml of a saturated aqueous solution of sodium hydrogencarbonate and the obtained mixture was stirred for 10 minutes. The formed precipitates were separated by filtration and washed once with ion-exchanged water, once with a saturated aqueous solution of sodium disulfite and then three times with ion-exchanged water. The washed precipitates were dried under heating at a reduced pressure and 0.84 g (the yield: 51%) of a light purple solid of 8,15-bis(p-biphenylyl)benzo[a]pentacene was obtained. The obtained product was purified by sublimation at 320° C. under 4.0×10−6 Torr for 2 hours and 450 mg of a deep purple amorphous solid was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([NH2:17])[N:7]=[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]3=2)[N:4]=1)=[CH2:2].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([NH2:17])[N:7]=[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]3=2)[N:4]=1)[CH3:2]
Reactant: C=Cc1ccc2c(n1)c(N)nc1ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1ccc2c(n1)c(N)nc1ccccc12
Reaction time: 8 h

Procedure:
To a solution of 3-vinylbenzo[f][1,7]naphthyridin-5-amine (Example 23) in ethyl acetate/ethanol (1:1, 0.07 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred overnight. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo giving 3-ethylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (acetone d-6): δ 8.93 (d, 1H), 8.41 (d, 1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.51-7.55 (dd, 1H), 7.30-7.34 (dd, 1H), 6.55 (br, 2H), 6.03 (q, 2H), 1.41 (t, 3H). LRMS [M+H]=224.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:9]=[C:8]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:18]3)=[CH:14][CH:13]=2)=[O:11])[S:7][C:6]=1[Br:27].Br[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45]>CC#N>[Br:27][C:6]1[S:7][C:8]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:18]3[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH:35]3[C:36](=[O:45])[C:37]4[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:43]3=[O:44])=[CH:14][CH:13]=2)=[O:11])=[CH:9][C:5]=1[CH2:4][C:3]([O:2][CH3:1])=[O:28]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1Br
Reactant: O=C1c2ccccc2C(=O)C1NCCCCBr
Solvent: CC#N
Product: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCNC4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Yield: 41.8 %

Procedure:
To a stirred solution of 453 mg (1 mmol) of methyl-(2-bromo-5-(2-phenyl-1H-indole-6-carbonyl)thiophene-3-yl)acetate in 10 mL of anhydrous CH3CN was added 1.25 g of CsF-Celite under N2, and then followed by 295 mg (1 mmol) 2-(4-bromobutylamino)-1H-indene-1,3(2H)-dione. The resulting mixture was refluxed for 5 h. The mixture was filtered and washed with CH3CN (5 mL×3), the filtrate was evaporated under reduced pressure, and the residue was purified by MPLC (EtOAc/Hex 1:4) to give 280 mg product as a yellow solid (yield 42%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[NH:19])([O-:18])=[O:17]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCSCc1cnccn1
Product: N=C(NCCSCc1cnccn1)N[N+](=O)[O-]

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]pyrazine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrazinylmethylthio)-ethyl]guanidine. Similarly by the procedure of Example 2 (iii), there is prepared N-methyl-N'-nitro-N"-[2-(2-pyrazinylmethylthio)ethyl]guanidine.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7]C2CCCCO2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([S:37]([O-:39])=[O:38])=[CH:32][C:31]=3[C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Li+]>>[Cl:36][C:35]1[C:30]2[O:29][C:26]3[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:22])[CH2:24][C:25]=3[C:31]=2[CH:32]=[C:33]([S:37]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:14][CH:15]=2)(=[O:39])=[O:38])[CH:34]=1
Reactant: Ic1ccc(COC2CCCCO2)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)[O-])cc3c2C1
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccc(CO)cc4)cc3c2C1
Yield: 7 %

Procedure:
The product of step A was coupled with lithium 2-(tert-butoxycarbonyl)-6-chloro-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-8-sulfinate following the procedure of Example 50, step A. The crude product was purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-((4-(hydroxymethyl)phenyl)sulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (30 mg, 7%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.02-7.89 (m, 3H), 7.82 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 4.77 (d, J=5.4 Hz, 2H), 4.56 (s, 2H), 3.83 (t, J=5.7 Hz, 2H), 2.97-2.85 (m, 2H) 1.50 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[CH2:9][O:10][CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([C@@H:8]([NH2:7])[CH2:9][O:10][CH3:11])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:15]=2[CH:23]=1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethyl]carbamic acid tert-butyl ester (419 mg, 1 mmol) in DCM (6 mL) was added TFA (3 mL) and the mixture was stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification: yellow oil (135 mg, 47%). LCMS (Method B): RT 1.71 min [M+H]+ 287.01.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:16]([NH:18][C:19]1[CH:31]=[CH:30][C:22]2[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:21]=2[CH:20]=1)=[O:17])([CH3:15])([CH3:14])[CH3:13].C(Cl)Cl>ClCCCl>[O:6]=[S:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:21]2[CH:20]=[C:19]([NH:18][C:16]([C:12]([CH3:15])([CH3:13])[CH3:14])=[O:17])[CH:31]=[CH:30][C:22]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)-c1ccccc1S2=O
Yield: 8.9 %

Procedure:
m-Chloroperoxybenzoic acid (50% wt/wt, 770 mg, 2.0 mmol) was added to a solution of 2-(t-butylcarbonylamino)dibenzothiophene (Example 2; 566 mg, 2.0 mmol) in 1,2-dichloroethane and the resultant mixture warmed at 80% for 16 hours then cooled and DCM was added (50 ml). The mixture was washed with 2 M sodium hydroxide, water and brine, dried and evaporated in vacuo to a brown gum. This was purified by chromatography eluting with 0-2% methanol in DCM. The impure product thus obtained was purified by preparative HPLC (Dynamax C-18 60A column eluted with 40-95% acetonitrile in water plus 0.1% trifluoroacetic acid) to obtain the product (53.5 mg) NMR: 9.59 (s, 1H), 8.35 (d, 1H), 8.03 (d, 1H), 7.97 (d, 1H), 7.93 (d, 1H), 7.80 (dd, 1H), 7.70 (t, 1H), 7.56 (t, 1H), 1.16 (s, 9H); m/z 300.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:16]2[NH:15][C:14](=O)[CH2:13][N:12]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[N:10]=[C:9]([CH3:27])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].CSC.B>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:16]2[NH:15][CH2:14][CH2:13][N:12]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[N:10]=[C:9]([CH3:27])[CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc2c1NC(=O)CN2c1c(C)cc(C)cc1C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCC(CC)Oc1cc(C)nc2c1NCCN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.5 %

Procedure:
A mixture of 8-(1-ethyl-propoxy)-6-methyl-4-(2,4,6-trimethyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (13 mg, 0.0354 mmol) and 2M borane dimethylsulfide complex (BH3.DMS) (0.044 ml, 0.0884 mmol) in 2 ml of dry THF was heated at reflux for 2 hours. The mixture was quenched with 0.2 ml of methanol and 0.2 ml of concentrated hydrochloric acid (HCl) and the resulting mixture was stirred at room temperature for 2 hours, and then concentrated to dryness. The residue was quenched with water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 14.7 mg of the title compound as a brown crystals. The crystals were purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 9 mg of the title compound as a colorless oil. 1H NMR (CDCl3) δ 6.93(s,2H), 6.02(s,1H), 4.18(m,1H), 3.62(m,2H), 3.44(m,2H), 2.31(s,3H), 2.12(s,9H), 1.71(m,4H), 0.98(t,6H)ppm.
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1([F:16])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1.Br[CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20]>C(Cl)Cl>[F:9][C:10]1([F:16])[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][C:19]([OH:21])=[O:20])[CH2:11]1
Reactant: FC1(F)CCCNC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Triethylamine (0.660 mL, 4.76 mmol) was added to a solution of 3,3-difluoropiperidine-HCl (500 mg, 3.17 mmol) and benzyl 2-bromoacetate (763 mg, 3.33 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was washed with 1 N aqueous sodium hydroxide and water, successively. The organic layer was concentrated and the residue was purified by flash column chromatography on silica gel (Hexane/EtOAc=25:1) to afford benzyl ester of 2-(3,3-difluoropiperidin-1-yl)acetic acid (486 mg, 56% yield) as a yellow oil.