Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:22])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]([SH:34])=[N:32][N:33]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[C:16]1([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:22])[C:2]([S:34][C:31]3[NH:30][C:29]([C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)=[N:33][N:32]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Reactant: Sc1nnc(-c2ccncc2)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Sc1nnc(-c2ccncc2)[nH]1
Temperature: 55 °C
Yield: 27 %

Procedure:
A solution of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (150 mg, 0.46 mmol, from Step 1 below), 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (82 mg, 0.46 mmol), and triethylamine (64 □L, 0.46 mmol) dissolved in DMF (5 mL) was heated to 55° C. under N2 for 8 h. The resulting mixture was concentrated and purified by Prep HPLC to give the title compound (58 mg, 27%) as a pale yellow solid. 1H NMR (DMSO-d6): δ 1.62-1.82 (m, 12H), 2.03-2.11 (m, 8H), 2.51 (m, 1H), 2.87 (d, 1H, J=17.5 Hz), 3.11 (d, 1H, J=17.5 Hz), 5.55 (s, 1H), 8.01 (d, 2H, J=5.8 Hz), 8.84 (d, 2H, J=5.8 Hz). ESIMS: MH+ 467.15
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.C(N(CC)C(C)C)(C)C>>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)c1ccc(NCC2CCCCO2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(ethylsulfonyl)-2-nitrobenzene (step C of Example 2), 2-aminomethyltetrahydropyran (Sciences Chimiques 1972, 3, 685-688) and N,N-diisopropylethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C@:20]2([CH3:31])[CH2:25][C@@H:24]([C:26]([F:29])([F:28])[F:27])[O:23][C:22]([NH2:30])=[N:21]2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1>>[NH2:30][C:22]1[O:23][C@H:24]([C:26]([F:28])([F:29])[F:27])[CH2:25][C@:20]([C:14]2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=[C:12]([NH:11][C:8](=[O:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH:13]=2)([CH3:31])[N:21]=1
Reactant: Cn1cc(N)cc([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)c1=O
Reactant: O=C(O)c1ccc(Cl)cn1
Product: Cn1cc(NC(=O)c2ccc(Cl)cn2)cc([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)c1=O

Procedure:
This step was performed using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-chloro-picolinic acid and 5-amino-3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-1-methylpyridin-2(1H)-one. MS m/z=444.0 [M+H]+. Calculated for C18H17ClF3N5O3: 443.8
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([F:17])[C:11]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)=[C:12]([F:17])[C:11]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCc1ccc(C=O)cc1
Reactant: CCCCCCCCOc1ccc(N)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(N=Cc2ccc(CCC)cc2)c(F)c1F

Procedure:
A mixture of 0.1 mol of 4-octyloxy-2,3-difluoroaniline (prepared from the corresponding amide by a Hoffmann rearrangement), 0.1 mol of 0.1 mol of 4-propylbenzaldehyde, 0.01 mol of p-toluenesulfonic acid and 200 ml of toluene is heated at the boiling point for 2 hours using a water separator. Customary working up gives (4 -octyloxy-2,3-difluorophenyl)-4-propylbenzylideneamine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([CH3:16])[CH:15]=1)([O-:9])=[O:8].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:16][C:14]1[CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1CSCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCSCC1

Procedure:
In the same manner as in Production Example 5-1, but using thiomorpholine in place of N-ethylpiperazine used in Production Example 5-1, using 5-nitro-2-fluorotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, crude 4-(2-methyl-4-nitrophenyl)thiomorpholine was obtained.
Reaction SMILES: C([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH:10]=[C:9]1[CH3:19])C1C=CC=CC=1.CC([O-])(C)C.[K+].O=O>C1COCC1.CS(C)=O>[CH3:18][O:17][C:12]1[C:11]2[CH:10]=[C:9]([CH3:19])[NH:8][C:16]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1cc(C)n2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1nccc2[nH]c(C)cc12

Procedure:
To a stirred solution of (1-benzyl-4-methoxy-2-methyl-1H-pyrrolo[3,2-c]pyridine 2 (0.887 mg, 3.52 mmol) in THF (10 mL), DMSO (2.5 mL), followed by KOtBu (25 mL, 1.0 M in THF) was added dropwise, and then the reaction mixture was treated with O2 for 15 min at room temperature, quenched with saturated NH4Cl (20 mL), extracted with EtOAc (3×60 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4 and evaporated. Flash chromatography of the residue over silica gel, using 20% EtOAc in hexanes to 40% EtOAc in hexanes) gave product 3 as a yellow solid. Yield: 560 mg (98%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[CH:3]=[C:4]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])=[CH:23][CH:22]=1
Reactant: NCc1ccc(Br)cc1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(Br)cc3)c2)nc1
Temperature: 80 °C
Reaction time: 14.5 h
Yield: 70.7 %

Procedure:
To a round-bottomed flask containing 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine (68.0 g, 259 mmol) and 4-bromobenzylamine (58 g, 259 mmol) in acetonitrile (680 mL) was added DIPEA (113 mL, 648 mmol). The stirred mixture was then heated to 80° Celsius. After 14.5 h, the mixture was cooled to RT and was concentrated to 261 g. The resulting residue was added to i-PrOH (900 mL) and heated to 70° Celsius until homogeneous. The solution was cooled to RT and the crystalline solids were isolated through filtration. The filter cake was washed with cold i-PrOH (200 mL), the solids were collected and dried in a vacuum oven at 40° Celsius for 3 days to give the title compound (78.4 g, 71%). MS (ESI): mass calcd. for C20H18BrN3O3, 427.1; m/z found, 428.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.66 (t, J=5.9, 1H), 8.36 (d, J=2.1, 1H), 8.16 (d, J=9.5, 1H), 7.57-7.37 (m, 3H), 7.27-7.23 (d incident with solvent signal, 1H), 7.22-7.13 (m, 2H), 6.34 (dd, J=9.5, 2.6, 1H), 6.18 (d, J=2.6, 1H), 5.12 (s, 2H), 4.44 (d, J=5.8, 2H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([C:37]([NH2:36])=[O:38])[CH2:27][CH2:28]4)[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Solvent: ClCCl
Product: NC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4SCc4cccnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
4-(8-Chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-1-(4-piperidine-acetyl)piperazine (270 mg, 0.591 mmol) was added to anhydrous CH2Cl2 (2.7 ml). TMSNCO (320 mg, 0.37 ml, 2.36 mmol) was added by syringe. The mixture was stirred at room temperature for 90 hours and then quenched with saturated NaHCO3. More water and CH2Cl2 were added, and the mixture was shaken and separated. The aqueous phase was extracted with CH2Cl2 (4×20 ml), and the combined organic phases were washed with brine, dried (Na2SO4), decanted and concentrated. The crude residue was purified by flash chromatography (5%MeOH/CH2Cl2 to 10%MeOH/CH2Cl2 /NH4OH) and the pure product was obtained (295 mg, 66%) MS (FAB, M+H)=529.
Reaction SMILES: Br/[CH:2]=[C:3]1\[C:4]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:5]=2[CH2:6][CH2:7][C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][N:9]=2.[F:19][C:20]1[CH:21]=[C:22]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[CH:23]=[C:24](/[CH:2]=[C:3]2\[C:4]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:5]=3[CH2:6][CH2:7][C:8]3[C:13]\2=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:25]=1
Reactant: CC1(C)OB(c2cc(F)cc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Fc1ccc2c(c1)CCc1ncccc1/C2=C/Br
Product: CS(=O)(=O)Nc1cc(F)cc(/C=C2\c3ccc(F)cc3CCc3ncccc32)c1
Yield: 66.7 %

Procedure:
Following procedures essentially as desctribed in Example 219, beginning with (E)-5-bromomethylene-8-fluoro-10,11-dihydro-benzo[4,5]cyclohepta[1,2-b]pyridine (50 mg, 0.16 mmol) and N-[3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (62 mg, 0.20 mmol). After work-up, purify the crude product by flash chromatography (50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) to provide 44 mg (65%) of purified product. LCMS (APCI-pos): 413.0 (M+H). LCMS (APCI-neg): 411.0 (M−H). Purity by LCMS 1 Area percent) 98%. 1HNMR (d6-DMSO, 400 MHz): δ9.91 (s, 1H), 8.42 (dd, 1H), 7.91 (dd, 1H), 7.29-7.25 (m, 2H), 6.92 (s, 2H), 6.90 (d, 1H), 6.77-6.74 (m, 2H), 6.52-6.49(m, 1H), 3.4-2.8 (m, 4H), 2.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Cl:9]N1C(=O)CCC1=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:9])=[C:4]([CH3:8])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(N)n1
Product: Cc1nc(N)ccc1Cl

Procedure:
In the manner described above in Example BBM-001-065, 2-amino-6-picoline, Acros Organics (1.08 g, 0.01 mol) is treated with N-chlorosuccinimide to give 2-amino-5-chloro-6-methylpyridine as a light-yellow solid (MP 73-74° C.).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[N:21]=[C:20]([S:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=3[F:36])[N:19]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][S:27][C:20]1[N:19]=[C:18]([NH:17][S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:16])=[O:15])[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[N:21]=1
Reactant: CCOc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-[[[2-[[(2,3-difluorophenyl)methyl]thio]-6-ethoxy-4-pyrimidinyl]amino]sulfonyl]-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from step ii) (0.24 g) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was evaporated, the residue was azeotroped with DCM (×2) and then purified by reverse phase HPLC eluting with acetonitrile/aq. 0.2% trifluoroacetic acid mixtures to give title compound as a white solid. Yield: 0.18 g
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:10]=3[S:9](=O)[C:8]=2[CH:20]=1)([O-])=O>C(O)C.[Pd]>[CH:12]1[C:11]2[C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:20][C:8]=3[S:9][C:10]=2[CH:15]=[C:14]([NH2:16])[CH:13]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)c1cc([N+](=O)[O-])ccc1-2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)sc1cc(N)ccc12

Procedure:
Two batches of the above solid 3,7-dinitro-dibenzothiophene 5-oxide was hydrogenated at 45 psi in ethanol (250 mL for each batch) with 10% Pd on carbon (0.46 g each batch) for 2 hours. Two batches were combined and filtered through CELITE to give an orange solution. Hydrogen chloride gas was bubbled into the solution to form precipitate (at pH 1). The precipitate was filtered and washed with small amount of ethanol and dried on vacuum to give an orange solid Dibenzothiophene-3,7-diamine (2.46 g). LCMS-EST: calc'd for C12H10N2S: 214.29. Found: 215.0 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:22][C:23]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Reaction time: 1 h
Yield: 65 %

Procedure:
50 g of 4-piperidine ethanol and 49.2 g of sodium hydrogencarbonate were dissolved in 480 ml of water, in which 55.2 ml of benzyloxycarbonyl chloride was gradually dropped under ice-cooling conditions, followed by agitation for 1 hour as it is. The reaction solution was extracted with chloroform and dried with anhydrous magnesium sulfate. The sulfate was filtered off and the solvent was distilled off, after which the resultant residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:hexane=30:70) to obtain 66.0 g of the captioned compound (yield: 65%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9]([N:12]=[C:13](Cl)[CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:16].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O>C(Cl)Cl>[CH2:17]([N:19]([CH2:20][CH3:21])[C:13](=[N:12][S:9]([C:5]1[CH:6]=[C:7]([Br:8])[C:2]([NH2:1])=[C:3]([Br:16])[CH:4]=1)(=[O:11])=[O:10])[CH3:14])[CH3:18]
Reactant: CC(Cl)=NS(=O)(=O)c1cc(Br)c(N)c(Br)c1
Reactant: CCNCC
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(C)=NS(=O)(=O)c1cc(Br)c(N)c(Br)c1

Procedure:
100 Mg. of crude N-(4-amino-3,5-dibromophenylsulfonyl) acetimidoyl chloride is stirred in 10 ml. of methylene chloride with 1 ml. of diethylamine at room temperature overnight. Volumes of water and methylene chloride equal to the volume of the reaction mixture are added, agitated and the layers separated. The organic layer is dried over magnesium sulfate and evaporated to dryness, in vacuo. The residue is taken up in 1 ml. of ethyl acetate and the dropwise addition of petroleum ether affords N,N-diethyl-N'-(4-amino-3,5-dibromophenylsulfonyl) acetamidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:31])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:16]=[N:15][C:14]([CH:13]([F:31])[F:12])=[N:19][CH:18]=1)[CH2:23][C:24]1([C:27]([F:30])([F:28])[F:29])[CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1)c1ccc(Cl)cc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,4-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=468.0, tR (minutes, Method F)=3.14. [α]D20=+32.40 (c=3.15 mg/mL,CHCl3)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C@:6]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[NH2:7].[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.O>[NH2:18][C:17]([NH:7][C@@:6]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[CH2:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([I:1])[CH:3]=1)=[O:16]
Reactant: COC(=O)[C@](C)(N)Cc1cccc(I)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@@](C)(Cc1cccc(I)c1)NC(N)=O
Temperature: 20 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
A mixture of methyl 3-iodo-α-methyl-D-phenylalaninate (0.73 g) in acetic acid (3 ml) and water (1 ml) was treated with sodium cyanate (0.4 g) and stirred for 2 days at 20° C. The solvents were removed under reduced pressure and the residue was diluted with EtOAc. The solution was washed with water, brine, dried (MgSO4) and evaporated to give the title compound (0.82 g) LCMS RT=2.74 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>O1CCOCC1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: BrCCCCCCOCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride in 1,4-dioxane was added benzyl alcohol in 1,4-dioxane over a period of 30 minutes at 80° C., and the mixture was stirred for 1 hour. The obtained alkoxide solution was added to a solution of 1,6-dibromohexane in 1,4-dioxane at room temperature. The mixture was stirred at 80° C. for 14 hours and insoluble materials were filtered off. The filtrate was concentrated and the residue was distilled under reduced pressure to give the object compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:15]2[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]([C:12]([F:11])([F:27])[F:26])[CH:14]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#Cc1nc(Br)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc1N

Procedure:
A stirred solution of 1.6 grams (0.008 mole) of 2-amino-3-cyano-5-bromopyrazine [prepared by the method of Taylor and Ray--JOC, 52, 3997 (1987)], 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid commercially available or prepared by the method of Thompson and Gaudino--JOC, 49, 5237 (1984)], 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene is heated at 90° C. for about 20 hours. After this time, the reaction mixture is stirred with 100 mL of water, and the organic layer is separated. The organic layer is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]pyrazine.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][N:24]([S:39]([C:35]5[CH:36]=[CH:37][CH:38]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:34]=5)(=[O:41])=[O:40])[CH2:23][CH2:22]4)=[O:20])[CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(c1cccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(S(=O)(=O)N2CCN(C(=O)c3cccc(-c4ccc(Oc5ccc(F)cc5)cc4)n3)CC2)c1
Yield: 84 %

Procedure:
According to the methodology described in Example 7, compound 6 (100 mg, 0.24 mmol), 3-methylsulfonylbenzenesulfonyl chloride (60 mg, 0.24 mmol), DIEA (0.1 mL, 0.7 mmol) and DCM (5 mL) were reacted to give compound 8 in 84% yield (LC/MS (m/z+H)=596; 1H NMR (CDCl3) δ ppm: 6.8-8.5 (m, 15H); 4.0 (m, 4H); 3.3 (m, 4H); 3.2 (s, 3H)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[O:12][CH3:13])[C:6]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:8]
Reactant: CCOc1cc(C(=O)O)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OCC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3,4-dimethoxy-5-ethoxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[S:16][CH2:15][C@H:14]2[C@:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])([CH2:10][O:11][C@@H:12]([CH2:17][OH:18])[CH2:13]2)[N:8]=1.[N+:26]([O-])([OH:28])=[O:27].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:6][C:7]1[S:16][CH2:15][C@H:14]2[C@:9]([C:19]3[CH:24]=[C:23]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:21][C:20]=3[F:25])([CH2:10][O:11][C@@H:12]([CH2:17][OH:18])[CH2:13]2)[N:8]=1
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CO)C[C@H]2CS1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@@H](CO)C[C@H]2CS1
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (2.5 ml) was added dropwise to a solution of [(4aR,6R,8aS)-2-amino-8a-(2-fluorophenyl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-6-yl]methanol (700 mg) in TFA (5 ml) in an ice bath. Then, fuming nitric acid (specific gravity: 1.52, 103 μl) was added dropwise at the same temperature, followed by stirring for one hour. The reaction mixture was poured into ice and made basic with a 5 N sodium hydroxide solution, followed by stirring at room temperature for two hours. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.0 g).