Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:6]=2[C:5]=1[C:14]([O:16]C)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=[N:21][CH:20]=1>>[CH3:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][N:27]2[C:14](=[O:16])[C:5]3[C:6]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:22]=[N:21][CH:20]=1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCCC2
Reactant: Cc1cncn1CCCN
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc3c(c2c1=O)CCCCC3

Procedure:
The compound was synthesized starting from methyl 5,6,7,8-tetrahydro-2-isothiocyanato-4H-cyclohepta[b]thiophene-3-carboxylate (0.10 g, 0.37 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.052 g, 0.37 mmol) as described above.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: Nc1nc(OCCCCO)nc2c1ncn2Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(OCCCCO)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
6-Amino-9-benzyl-2-(4-hydroxybutoxy)purine (200 mg, 0.638 mmol) and bromine (1.0 ml) were dissolved in methylene chloride (50 ml). The solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (213 mg, yield 85%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[C:50](OC(=O)C)(=[O:52])[CH3:51]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][N:13]([C:50](=[O:52])[CH3:51])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1
Reactant: COc1ccccc1CNC[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1CN(C[C@@H](Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirring solution of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mol) in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Cl:42][C:43]1[C:44]([F:51])=[C:45]([CH:47]=[CH:48][C:49]=1[Cl:50])[NH2:46]>>[Cl:42][C:43]1[C:44]([F:51])=[C:45]([NH:46][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=3)[N:30]=[CH:29][N:28]=2)[CH:47]=[CH:48][C:49]=1[Cl:50]
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)c(Cl)c1F
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3ccc(Cl)c(Cl)c3F)c2cc1N

Procedure:
Starting material: N4-(3,4-dichloro-2-fluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 3,4-dichloro-2-fluoro-aniline; other starting materials were prepared as example 1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8](Cl)=[O:9].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(Cl)COc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCCNC(=O)COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution of 6.44 g of the product of Step C in 60 ml of chloroform was added at +10° C. to a solution of 10.2 g of N-(tert-butoxycarbonyl)-1,4-diamino-butane in 150 ml of chloroform and after stirring for 2 hours at room temperature, the mixture was evaporated to dryness under reduced pressure. The product was added to water and vacuum filtered to obtain 7.85 g of the desired product melting at 86° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:5][CH:4]1[C:18]1[N:22]2[C:23]3[CH:29]=[CH:28][NH:27][C:24]=3[N:25]=[CH:26][C:21]2=[N:20][N:19]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH-].[Na+].[H-].[Na+].[CH3:67][Si:68]([CH2:71][CH2:72][O:73][CH2:74]Cl)([CH3:70])[CH3:69]>O1CCOCC1>[CH2:1]([CH:3]1[CH2:7][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:5][CH:4]1[C:18]1[N:22]2[C:23]3[CH:29]=[CH:28][N:27]([CH2:74][O:73][CH2:72][CH2:71][Si:68]([CH3:70])([CH3:69])[CH3:67])[C:24]=3[N:25]=[CH:26][C:21]2=[N:20][N:19]=1)[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCC1CC(OCc2ccc(OC)cc2)CC1c1nnc2cnc3[nH]ccc3n12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC1CC(OCc2ccc(OC)cc2)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a suspension of 1-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]-triazolo[4,3-a]pyrazine (0.323 g, 0.825 mmol, prepared using Z from Preparation #EE.1, A from Example #1, Step D, HATU, and TEA, B with DIEA, D with NaOH) in 1,4-dioxane (2.5 mL) was added NaH (0.035 g, 0.866 mmol, 60% dispersion in mineral oil) in portions. The reaction mixture was stirred at ambient temperature for about 30 min. SEM-Cl (0.15 mL, 0.83 mmol) was added. After about 30 min, the solvent was removed and the residue was partitioned between EtOAc (12 mL) and water (2 mL). The organic layer was separated and concd under reduced pressure. The residue was purified using silica gel chromatography (40 g) eluting with a gradient of 0-60% EtOAc in DCM to give 1-(2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.372 g, 86%): LC/MS (Table 1, Method b) Rt=2.96 min; MS m/z: 522 (M+H)+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[CH3:46][N:47]([C@H:61]1[CH2:65][CH2:64][NH:63][CH2:62]1)[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:63]2[CH2:64][CH2:65][C@H:61]([N:47]([CH3:46])[C:48]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=3)=[O:49])[CH2:62]2)=[O:29])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CN(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCNC1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 76 %

Procedure:
Following a procedure similar to that described in Preparation 18, but using 1.21 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 343 mg of pivaloyl chloride and 1.27 g of (3S)-3-[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]pyrrolidine trifluoroacetate, 1.21 g of the title compound were obtained as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[C:10]=2[OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])(=O)C.[Na+].[Br:23]Br>C(O)(=O)C>[Br:23][C:13]1[CH:12]=[C:11]([CH:15]=[O:16])[C:10]([OH:17])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: O=Cc1cccc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cc(Br)cc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 8 h

Procedure:
To a solution of 3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (400 mg, 1.5 mmol) and sodium acetate (185 mg, 1.5 mmol) in acetic acid (20 mL), bromine (100 uL, 1.5 mmol) was added slowly. The resulted solution was stirred overnight. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with 5% aqueous sodium thiosulfate, the organic layer dried (MgSO4), filtered and concentrated under reduced pressure to give 5-bromo-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])=[CH:6][CH:5]=1
Reactant: O=C(N1CCCc2ccc([N+](=O)[O-])cc21)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Reaction time: 24 h
Yield: 96 %

Procedure:
A mixture of 7-nitro-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D4) (1.51 g, 5.5 mmol) and 10% palladium on charcoal (150 mg, 54% water) in methanol (80 ml) was hydrogenated at atmospheric pressure and ambient temperature for 24 h. The catalyst was removed by filtration and was washed with further methanol. The combined filtrated and washings were concentrated in vacuo to give the title compound as a pale orange solid (1.29 g). 1H NMR (250 MHz, CDCl3) δ (ppm): 7.05 (br, 1H), 6.95 (d, 1H), 6.54 (dd, 1H), 3.78 (m, 2H), 3.65 (br, 2H), 2.74 (br, 2H), 2.03 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:21])[CH:3]=1.C(O)(=O)C.[N:26]([O-])=O.[Na+].C(Cl)Cl.C(OCC)(=O)C>O1CCCC1.O>[F:21][C:4]1[C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:10][C:11]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:26]=[N:1][C:2]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1ccccc1Nc1cc(NC(C)=O)c(F)cc1N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1nnc2cc(F)c(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4'-amino-2'-fluoro-5'-(o-methoxyanilino)acetanilide (11.0 g, 0.038 mol) in tetrahydrofuran is added dropwise to a 50% acetic acid solution at 0° C. To the resultant mixture, a solution of sodium nitrite (5.51 g, 0.080 mol) in water is added dropwise. After the addition is complete, the reaction mixture is stirred at room temperature for 2 hours and filtered to obtain a solid. The filtrate is extracted with ethyl acetate and the organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark solid. Flash column chromatography of the combined solids using silica gel and a (3:1) methylene chloride/ethyl acetate solution gives the title product as a greenish-brown solid, mp 174°-175° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:11])[C:3]([O:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[O:4].[NH2:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:28])=[C:23]([Cl:36])[CH:22]=1.O.CCOC(C)=O>N1C=CC=CC=1>[CH3:11][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:28])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[C:23]([Cl:36])[CH:22]=1)=[O:10])=[O:4]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2N)cc1Cl
Reactant: C=C(C)C(=O)OCCN=C=O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OCCNC(=O)Nc1cc(Br)ccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Isocyanatoethyl 2-methylacrylate (0.31 g, 2.2 mmol) was slowly added to a solution of {4-[(2-amino-4-bromophenyl)amino]-2-chlorophenyl}(2-methylphenyl)methanone (0.60 g, 1.44 mmol)(disclosed in WO 01/05744) in dry pyridine (3.00 mL). The solution was stirred at room temperature for 6 h after which it was poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using petroleum ether/EtOAc 4:1 as the eluent to afford the title compound as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21].[H][H]>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21]
Reactant: [H][H]
Reactant: O=C1c2ccccc2CN1CC#Cc1ccc(F)cc1F
Agent: [Pd]
Solvent: CCO
Product: O=C1c2ccccc2CN1CCCc1ccc(F)cc1F

Procedure:
2-[3-(2,4-Difluoro-phenyl)-prop-2-ynyl]-2,3-dihydro-isoindol-1-one was dissolved in EtOH (5 mL) and a small amount of 10% Pd/C was added. A hydrogen balloon was attached to the flask and the system was evacuated and flushed three times. The reaction was allowed to stir for twenty-two hours. The reaction mixture was filtered and concentrated to provide the title compound as a colourless oil (13.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10].C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CO>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([CH2:24][NH:25][CH3:26])=[CH:13]1)(=[O:11])=[O:10]
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2cc(F)ccc2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ({1-[(2,5-difluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (160 mg) was dissolved in ethyl acetate (5 mL) and methanol (3 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give the title compound as a free base. The free base was dissolved in ethyl acetate. 4 mol/L Hydrogen chloride-ethyl acetate solution was added and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 45.9 mg, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][OH:13])[C@@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][O:13][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][O:21]3)[C@@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@@]2(CO)C[C@H]2N1C(=O)OC(C)(C)C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@@]2(COC3CCCCO3)C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (1R,3S,5S)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester (500 mg, 1.75 mmol), 3,4-dihydro-2H-pyran (176 μL, 1.93 mmol) and TsOH.H2O (33 mg, 0.17 mmol) in CH2Cl2 (6 mL) was stirred 3 h at RT. Then poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). Colorless oil. TLC, Rf (EtOAc)=0.85; MS (UPLC/MS): 370.4 [M+H]+, 387.4 [M+H2O]+; tR (HPLC conditions f): 2.28 min.
Reaction SMILES: [CH:1]([CH:14]1[NH:23][CH:22]2[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[N:16](C(OC(C)(C)C)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>>[ClH:31].[ClH:31].[CH:1]([CH:14]1[CH2:15][NH:16][CH:17]2[CH:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:23]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(c2ccccc2)c2ccccc2)NC2CCCCC21
Agent: Cl
Product: c1ccc(C(c2ccccc2)C2CNC3CCCCC3N2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-Butyl (3RS,4aSR,8aRS)-3-benzhydryloctahydroquinoxaline-1-carboxylate (100 mg) was dissolved in hydrogen chloride (5 ml, 4N solution in ethyl acetate) and the mixture was stirred at ambient temperature for 3 hours. The volatile materials were removed under reduced pressure to give (2RS,4aRS,8aSR)-2-benzhydryldecahydroquinoxaline dihydrochloride, which was dissolved in water and washed with ethyl acetate. The aqueous phase was adjusted to pH 9-10 and extracted with ethyl acetate three times. The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give (2RS,4aRS,8aSR)-2-benzhydryldecahydroquinoxaline (88 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:14]1([N:13]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=2)[CH3:11])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Nc1cccc2ccccc12
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(C(C)=Nc2cccc3ccccc23)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.6 %

Procedure:
2,6-Diacetylpyridine (5.49 g, 33.6 mmol) and 1-aminonaphthalene (4.8 g, 33.5 mmol) were dissolved in 100 ml of toluene. To this solution molecular sieves (4 Å) were added. After standing for 20 hours at room temperature, the mixture was filtered. The solvent was removed in vacuo. The resulting mixture of 2,6-diacetylpyridine, 2,6-bis-[1-(1-naphthylimino)ethyl] pyridine and 2-[1-(1-naphthylimino)ethyl]-6-acetylpyridine was dissolved in 50 ml THF. The diiminepyridine by-product 2,6-bis-[1-(1-naphthylimino)ethyl]pyridine was removed by selective complexation to a metal halide. FeCl2 (0.79 g , 6.23 mmol) was added in an inert atmosphere. After stirring for 16 hours at room temperature, the solvent was removed in vacuo. Toluene (100 ml) was added to the resulting mixture. The precipitated complex was filtered off over a small layer of silica, yielding a yellow solution. The solvent was removed vacuo. Crystallisation from ethanol yielded 3.25 g of 2-[1-(1-naphthylimino)ethyl]-6-acetylpyridine (6) (33.6%). 1H-NMR (CDCl3) δ 8.65 (d, 1H, Py-Hm), 8.15 (d, 1H, Py-Hm), 7.95 (t, 1H, Py-Hp), 7.87 (d, 1H, ArH), 7.76 (d, 1H, ArH), 7.64 (d, 1H, ArH), 7.4-7.6 (m, 3H, ArH), 6.82 (d, 1H, ArH), 2.79 (s, 3H, Me), 2.38 (s, 3H, Me).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18]B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(O)C.C1(C)C=CC=CC=1>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([CH3:18])[N:7]=1
Reactant: CB(O)O
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc(C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 40.7 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenyl-pyrrolo[3,2-d]pyrimidine (Example 1(e)) (80 mg, 0.33 mmol), methylboronic acid (Aldrich Chemical Company) (49 mg, 0.82 mmol), tris(dibenzylideneacetone) dipalladium(0) (Aldrich Chemical Company) (9.4 mg, 0.0103 mmol) and triphenylphosphine (Aldrich Chemical Company) (10.8 mg, 0.042 mmol) in a mixed solvent (1000 μL of toluene, 500 μL of 1.0 M Na2CO3, and 250 μL of ethanol) was heated at reflux under N2 overnight. Upon cooling to the room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with CHCl3 (4×40 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated with a rotary evaporator. This material was purified by preparative thin layer chromatography on silica gel with 1:1 THF:hexanes as eluant to afford 30 mg (62%) of the title compound as a yellow solid. 1H NMR (CDCl3; 400 MHz): δ 8.38 (s, 1), 7.74 (d, 2, J=7.0), 7.53 (t, 2, J=7.0), 7.45 (t, 1, J=7.0), 6.87 (d, 1, J=1.7), 2.79 (s, 3), 2.74 (s, 3). MS m/z: 224 (M+1), 222 (M−1).