Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27](C(OCC4C=CC=CC=4)=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cc2)c2ccccc21
Yield: 95.7 %

Procedure:
3.5 g of 4-[4-(4-(benzyloxycarbonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in a 250 ml three-necked flask under an inert atmosphere. 66 ml of MeOH, then 1.67 g of ammonium formate followed by 1.41 g of 10% Pd/C (50% in water), are added. The mixture is brought to reflux of the methanol for 1 h 30 minutes and then brought back to ambient temperature. It is filtered on a Whatman filter under an inert atmosphere and then rinsing is carried out numerous times with methanol. The methanol is evaporated under reduced pressure. The mixture is taken up in dichloromethane and the organic phase is washed with the minimum amount of water. The organic phase is dried over sodium sulphate, filtered through a sintered glass filter and evaporated under reduced pressure. 2.5 g of 4-(4-(piperazin-1-yl)phenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH:24](=O)[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:24]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-:21])=[O:20])[CH:6]=2)[C:2]([CH3:23])([CH3:1])[CH2:3]1)[CH3:25]
Reactant: CC=O
Reactant: CC1(C)CNc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(C)(C)c2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21

Procedure:
N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-nitro-benzamide (Step B) (300 mg, 0.96 mmol) was treated with acetaldehyde (70 μL) and NaBH(OAc)3 (300 mg, 1.4 mmol) in CH2Cl2 (50 mL) overnight. After drying in vacuo, the reaction mixture was purified via flash chromatography on silica gel using EtOAc to afford the desired compound.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C[O-].[Na+].[CH2:14]([OH:16])[CH3:15].C1(C)C=CC=CC=1>CO.C(OCC)(=O)C>[C:14]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)(=[O:16])[CH3:15]
Reactant: CCO
Reactant: c1cc2c(s1)CCNC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
35.1 g (200 mmole) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and 38.57 g (200 mmole) of 28% w/v sodium methoxide in methanol were added to 200 ml of ethanol, and the resulting mixture was stirred at room temperature for 1 hour. The inorganic salt thus precipitated was filtered off, and the filtrate was concentrated to dryness by evaporation under reduced pressure. 50 ml of acetic anhydride were added all at once, whilst stirring, to the residue, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness by evaporation under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography, using a 6:4 by volume mixture of toluene and ethyl acetate as the eluent, to give 29.32 g of the title compound as a yellow oil.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([NH:16][S:17]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:5]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].[CH3:35][OH:36]>>[CH3:35][O:36][C:4]1[N:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([NH:16][S:17]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:5]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCC(C)(C)C
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCC(C)(C)C)nc(-c2ncccn2)nc1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Sodium hydride (80% oil dispersion 132 mg) was cautiously added to a suspension of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-3,3-dimethyl-1-butanesulfonamide (Preparation 2)(420 mg) in dry methanol (12 ml) divided equally between two 10 ml Wheaton reacti-vials™, and the resulting mixtures stirred at 100° C. for 3 hours. The reactions were then combined and partitioned between ethyl acetate (40 ml) and 2N aqueous hydrochloric acid (20 ml) and the organic phase separated. The aqueous was extracted with ethyl acetate (20 ml) and the organic phases combined, washed (water 2×20 ml), dried (Na2SO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of dichloromethane:methanol 99:1 changing to 97:3 gave N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-3,3-dimethyl-1-butanesulfonamide as an off-white coloured foam (265 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>O1CCOCC1.ClCCl.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Ni]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(N)cc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
N-(3-nitro-5-trifluoromethyl-phenyl)-methylsulfonamide (0.1 g; 0.4 mmol) ammonium formate (0.1 g; 1.8 mmol) and Raney-Nickel (16 mg) were dissolved in 0.4 mL of dioxane. The reaction was heated to 140° C. for 6 minutes in a micro wave reactor. The mixture was then diluted with dichloromethane, filtrated and the filtrate concentrated. 70 mg (0.27 mmol; 68% yield) of an orange oil were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[NH2:18].[C:19]([OH:27])(=[O:26])[C:20]([CH2:22][C:23](O)=[O:24])=[CH2:21]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[N:18]1[C:23](=[O:24])[CH2:22][CH:20]([C:19]([OH:27])=[O:26])[CH2:21]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1cc(F)c(OCc2cccc(F)c2)cc1F
Product: O=C(O)C1CC(=O)N(c2cc(F)c(OCc3cccc(F)c3)cc2F)C1
Yield: 34.5 %

Procedure:
In an analogous manner to that described in Example 1a), 2,5-difluoro-4-(3-fluorobenzyloxy)-phenylamine was reacted with itaconic acid to yield (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (34.5% of theory) as a grey solid; MS: m/e=363 (M−H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:20]([O:19][C:17]([NH:16][C@@H:9]1[C:8]2[C:13](=[C:14]([CH3:15])[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc2c(c1C)SCC[C@@H]2NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(C(=O)O)ccc2c1SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 84.7 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (S)-4-(tert-butoxycarbonylamino)-8-methylthiochromane-7-carboxylic acid methyl ester (5.00 g) and potassium carbonate (6.13 g), the objective (S)-4-(tert-butoxycarbonylamino)-8-methylthiochromane-7-carboxylic acid (4.06 g) was obtained as a colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:11])=[C:7]([CH:10]=1)[CH2:8]O.O.[BrH:13]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:11])=[C:7]([CH:10]=1)[CH2:8][Br:13]
Reactant: Br
Reactant: COc1ccc(Br)c(CO)c1
Solvent: O
Product: COc1ccc(Br)c(CBr)c1
Temperature: 25 °C

Procedure:
5-Methoxy-2-bromobenzyl alcohol (79.5 g, 0.37 mol) is dissolved in 48% HBr (400 mL) and heated to reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and poured into water (1500 mL). The solution is extracted with EtOAc (2×500 mL). The combined organic layers are dried (MgSO4) and concentrated by rotary evaporator. The crude material is then purified using flash chromatography (CH2Cl2/hexanes, from 1:1 to 4:1) to give 5-methoxy-2-bromobenzyl bromide.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:26]=[C:25]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)C>O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:26]=[C:25]([N:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 70 °C
Yield: 94.5 %

Procedure:
Potassium hydroxide (3.79 g, 67.5 mmol) in water (135 mL) was added to a mixture of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(N,N-dimethylamino)-benzoate (5.11 g, 13.5 mmol) and ethanol. The reaction was heated to 70° C. for 14 hours. The ethanol was removed in vacuo. The resulting aqueous mixture was cooled to 5° C., acidified with satd citric acid, filtered with water wash, and vacuum dried to give the desired product as a white solid (4.65 g, 95%).
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13]C)=[O:11])[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.C(N(CC)CC)C.[CH2:22]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH2:9][C:10]([O:12][CH3:13])=[O:11])([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:3]1
Reactant: CCOC(=O)CC1(N)CCCN(C)C1
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OC)CCCN(C)C2)cc1
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(3-amino-1-methylpiperidin-3-yl)acetate (52 mg, 0.28 mmol) and triethylamine (0.2 mL, 1.44 mmol) in dichlormethane (15 mL) was treated with 4-n-pentylbenzenesulfonly chloride (120 mg, 0.487 mmol). The resulting mixture was stirred overnight. After removal of the volatiles, the residue was redissolved in dichloromethane, washed with sat. NaHCO3, dried (Na2SO4), evaporated and purified by flash chromatography (eluent: EtOAc/hex 1:1 to EtOAc) to give the title compound. (95 mg, 86%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, 2H, J=8.0 Hz), 7.27 (d, 2H, J=8.0 Hz), 5.67 (brs, 1H), 3.55 (s, 3H), 2.84 (d, 1H, J=11.6 Hz), 2.73-2.60 (m, 4H), 2.47 (brs, 1H), 2.20-1.92 (m, 6H; NCH3 and 3H), 1.70-1.57 (m, 3H), 1.48-1.27 (m, 6H), 0.88 (t, 3H, J=7.2 Hz); MS 397.2 ESI [M+H]+, calcd for [C20H32N2O4S+H]+ 397.22
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.C[O:9][C:10]1[C:11](=[O:28])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:13][N:14]([CH3:16])[CH:15]=1.O>C(#N)C>[OH:9][C:10]1[C:11](=[O:28])[C:12]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:13][N:14]([CH3:16])[CH:15]=1
Reactant: COc1cn(C)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cn1cc(O)c(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of sodium iodide (3.75 g) in acetonitrile (150 mL) was added chlorotrimethylsilane (3.17 mL) with stirring at room temperature, and the mixture was stirred for min. Then, 5-methoxy-1-methyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (1.41 g) was added, and the mixture was stirred for 30 min at the same temperature, and further refluxed for 3 hr. The reaction mixture was allowed to cool to room temperature, poured into water and the mixture was stirred for 30 min. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate-diisopropyl ether, collected by filtration, and dried to give the title compound (1.032 g) as white needles.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:20](Cl)(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(Cl)(=O)OCC>C(Cl)Cl>[CH2:36]([C:37]1[O:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:9]=2[N:8]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2c(OC)cccc2c(=O)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
Triethylamine (5.30 ml) was added to a suspension of 2-amino-3-methoxybenzoic acid (3.00 g) in methylene chloride (30 ml). The mixture was cooled with ice and stearoyl chloride (5.44 g) was dropwise added thereto. The reaction mixture was stirred for 2.5 hours at room temperature and then cooled with ice. Then, triethylamine (2.80 ml) and ethyl chlorocarbonate (1.88 ml) were added to the reaction mixture successively. The reaction mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature successively, and then concentrated. The residue, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 150 g, chloroform-hexane), thereby yielding 3.73 g of the aimed compound as colorless solid.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:8]1[C:9](=[O:24])[CH2:10][CH:11]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:12][C:13]=1[OH:14])[CH2:6][CH3:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(C(C)=O)C>[C:31]([O:24][C:9]1[CH2:10][CH:11]([C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[CH2:12][C:13](=[O:14])[C:8]=1[C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][CH3:7])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC(c2c(C)cc(C)cc2C)CC1=O
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A mixture of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (2.4 g), anhydrous methyl ethyl ketone (25 ml) and anhydrous potassium carbonate (1.65 g) was treated dropwise, with stirring, with benzoyl chloride (1.12 g). The mixture was heated under reflux with stirring for a period of 30 minutes and then filtered. The residue was washed with diethyl ether and the solvent from the combined filtrate and washings was evaporated under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed twice with water, dried, and the solvent was evaporated under reduced pressure to give a dark brown oil. The oil was purified by chromatography on preparative thin layer chromatography plates (silica gel; eluent hexane/diethyl ether 75:25) to give 3-benzoyloxy-2-[1-(ethoxyimino)propyl]-5-mesitylcyclohex-2-en-1-one (1.9 g).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:30])=[C:5]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8]>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[S:3][C:4]([Br:30])=[C:5]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Br)sc(Br)c2Cc2cccc(Cl)c2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H](NC(=O)c1c(Br)sc(Br)c1Cc1cccc(Cl)c1)c1ccc(C(=O)O)cc1

Procedure:
Methyl 4-[(1S)-1-({[2,5-dibromo-4-(3-chlorobenzyl)-3-thienyl]carbonyl}amino)ethyl]benzoate from Example 5, Step 1 (27.0 mg, 0.0472 mmol) was reacted under conditions similar to Example 1, Step 11. After trituration of the crude product in 1:9 EtOAc/hexane, the desired product was obtained as a white solid. MS (−APCI): m/z 554 (M−1)−.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].[CH2:12]([O-])[CH2:13][CH3:14].[Na+].C(O)CC>>[CH2:12]([S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:13][CH3:14]
Reactant: Sc1ccc2ccccc2c1
Reactant: CCC[O-]
Agent: [Na+]
Solvent: CCCO
Product: CCCSc1ccc2ccccc2c1
Reaction time: 10 h
Yield: 93.8 %

Procedure:
50 g (0.31 mole) of naphth-2-yl mercaptan were introduced into a solution of 29.5 g (0.36 mole) of sodium n-propanolate and 800 ml (10.6 moles) of n-propanol, and the mixture was heated from 25° to 150° C. in the course of 60 minutes under a carbon monoxide pressure of 300 bar in a 1.2 liter stirred autoclave, and then kept at this temperature for 10 hours. The mixture which emerged from the reactor was distilled to give 58.8 g (95% of theory) of naphth-2-yl n-propyl thioether of boiling point 115°-120° C./0.6 mbar.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[C:28]1[N:29]=[CH:30][S:31][CH:32]=1>>[C:26]([C:23]1[C:22]([C:28]2[N:29]=[CH:30][S:31][CH:32]=2)=[C:21]([NH:20][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: N#Cc1csc(N)c1-c1cscn1
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1cscn1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.047 g, 0.17 mmol) and 5-amino-4-(thiazol-4-yl)thiophene-3-carbonitrile (0.024 g, 0.12 mmol) according to protocol A. The desired product was submitted to prep HPLC for further purification. Retention time (min)=7.57, method [7], MS (ESI) 461.1 (M+H). 1H NMR (CDCl3) δ 12.73 (s, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.92-7.89 (m, 2H), 7.89 (d, J=9.3 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J=8.9 Hz, 1H), 6.96 (d, J=9.3 Hz, 1H), 5.30 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[NH:38][C:37]([C@@H:39]5[CH2:43][CH2:42][CH2:41][N:40]5C(OC(C)(C)C)=O)=[N:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:51][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1)[C:62]([OH:64])=O)=[O:59].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>C(Cl)Cl.CO.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[NH:38][C:37]([C@@H:39]5[CH2:43][CH2:42][CH2:41][N:40]5[C:62](=[O:64])[C@@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[CH:65]5[CH2:70][CH2:69][O:68][CH2:67][CH2:66]5)=[N:36][CH:35]=3)=[CH:32][CH:33]=2)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:51][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Temperature: 35 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
(S)-tert-butyl 2-(5-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (73 mg, 0.10 mmol) in DCM (3 mL) and MeOH (3 mL) was added HCl (4M in dioxane, 0.5 mL). The solution stirred for 3 h at 35° C., after which the solvent was removed. The intermediate (31 mg, 0.13 mmol) was dissolved in DMF (1 mL). (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (16 mg, 0.05 mmol), HATU (19 mg, 0.05 mmol), and DIPEA (0.04 mL, 0.25 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (27.6 mg). LCMS-ESI+: calc'd for C46H54N8O7: 830.97 (M+); Found: 832.56 (M+H+).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].N.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1/[N:20]=[C:21](\[C:31]#[N:32])/[C:22]1[S:30][C:25]2=[N:26][CH:27]=[CH:28][N:29]=[C:24]2[CH:23]=1>O.O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[C:12]([NH:20][CH:21]([C:22]2[S:30][C:25]3=[N:26][CH:27]=[CH:28][N:29]=[C:24]3[CH:23]=2)[C:31]#[N:32])[CH:13]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1/N=C(\C#N)c1cc2nccnc2s1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N)cc1NC(C#N)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
To a solution of sodium hydrosulfite (434 mg, 2.493 mmol) in water (3 mL) was added ammonia (0.561 mL, 3.64 mmol) and then compound 77 (62 mg, 0.192 mmol) in dioxane (3 mL). The reaction was stirred at rt. for 4 h. Quenched with water and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated to give compound 2-(5-amino-2-methylphenylamino)-2-(thieno[2,3-b]pyrazin-6-yl)acetonitrile 78 (48 mg, 85%) which was used without further purification. (m/z)=296 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[NH:9][N:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:8]1[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:9]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Product: CC(=O)n1nc(-c2cnccn2)nc1-c1cnccn1

Procedure:
A suspension of 3,5dipyrazinyl-1,2,4-triazole (0.5 grams) in 20 ml. of acetic anhydride is heated on a steam bath for 17 hours. The resulting solution is filtered and concentrated to a solid. After recrystallization from benzene-hexane, 250 mg. of 1-acetyl-3,5-dipyrazinyl-1,2,4-triazole is obtained, m.p. 128°-130° C.