Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH:16]=[N:15]2)[CH2:10][C@H:9]1[CH3:33])=[O:7])[CH3:4].CCO>[Pd].CCOC(C)=O>[CH2:3]([O:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:18]([C:19]([F:20])([F:21])[F:22])=[C:17]([C:23]([OH:25])=[O:24])[CH:16]=[N:15]2)[CH2:10][C@H:9]1[CH3:33])=[O:7])[CH3:4]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)C[C@H]1C
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@H]1C
Reaction time: 2.5 h
Yield: 85.2 %

Procedure:
A pressurized vial was charged with palladium 10 wt. % (dry basis) on activated carbon, wet (1.367 g, 1.284 mmol) while under a stream of N2 (gas). Then a solution of benzyl 1-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (5.631 g, 12.84 mmol) in a 1:1 mixture of EtOH (32.1 ml)/EtOAc (32.1 ml) was added into the vial. The reaction mixture atmosphere was purged with hydrogen gas (3×). The reaction was stirred vigorously under hydrogenation (35 psi) conditions for 2.5 h. The progress of the reaction was monitored by LC/MS, which suggested reaction completion LCMS (ESI) m/z 371.2 (M+Na)+. The mixture was filtered through a plug of celite and the filtrate was concentrated in-vacuo. The residue was diluted with hexane and agitated. The precipitate was collected by filtration and the solids were rinsed with hexane. This gave 1-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (3.810 g, 10.94 mmol, 85% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91-8.21 (m, 1H), 4.47-4.69 (m, 1H), 4.01-4.16 (m, 2H), 2.56-2.70 (m, 1H), 2.12 (dt, J=4.21, 12.37 Hz, 1H), 1.93-2.06 (m, 2H), 1.71-1.90 (m, 3H), 1.19 (t, J=7.04 Hz, 3H), 0.92 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 371.2 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][N:7]=1)=[O:4].CN(C)[CH:22]=[O:23]>C1COCC1>[CH:22]([C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1])=[N:7][CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=[O:23]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2ccccc2)cn1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(-c2ccccc2)cc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
2,2-dimethyl-N-(5-phenylpyridin-2-yl)propanamide (2.5 g, 9.83 mmol) was dissolved in 80 mL of dry THF and cooled to 0° C. N-Butyl lithium (2.5 M in hexanes) (9.8 mL, 24.57 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 2 hours and then N,N-dimethylformamide (3.6 g, 49.15 mmol) was added. The reaction mixture was removed from the cold bath and allowed to warm to room temperature. After 30 minutes the reaction was quenched with water. The mixture was extracted with EtOAc and dried over MgSO4. The solvent was removed and the residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (2:1) to afford N-(3-formyl-5-phenylpyridin-2-yl)-2,2-dimethylpropanamide (1.87 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.O/[N:53]=[C:54](\[NH2:62])/[CH2:55][S:56]([CH2:59][CH2:60][CH3:61])(=[O:58])=[O:57]>ClCCl.O>[NH2:62]/[C:54](=[N:53]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[CH2:55][S:56]([CH2:59][CH2:60][CH3:61])(=[O:58])=[O:57]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CCCS(=O)(=O)C/C(N)=N/O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCS(=O)(=O)C/C(N)=N/OC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
A solution of (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (354 mg, 1.85 mmol), N-methylmorpholine (203 □1,1.85 mmol) and 1-hydroxybenzotriazole hydrate (227 mg, 1.67 mmol) in dichloromethane (20 ml) was treated with (1Z)-N′-hydroxy-2-(propylsulfonyl)ethanimidamide (300 mg, 1.67 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and stirred for 20 minutes. The layers were separated via a 5 micron filter cartridge. The organic solvent was removed under reduced pressure to afford the title compound as a yellow solid (760 mg).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[N:14][N:13](O)[C:12]=3[CH:17]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[H][H]>[Pt].CO>[ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:15][N:14]=[N:13][C:12]=3[CH:17]=2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: [H][H]
Reactant: On1nnc2ccc(Cn3ccnc3)cc21
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: c1cn(Cc2ccc3[nH]nnc3c2)cn1
Yield: 72 %

Procedure:
A mixture of 4.3 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol monohydrochloride and 120 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized twice from ethanol. The product was filtered off and dried, yielding 2.9 parts (72%) of 5-(1H-imidazol-1-ylmethyl)-1H-benzotriazole monohydrochloride; mp. 230.4° C. (compound 234).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6]([C:8]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:13][CH2:12][CH2:11][N:10](C(OCC(Cl)(Cl)Cl)=O)[CH2:9]1)=[O:7].C([O-])(=O)C.[NH4+]>O1CCCC1.[Zn]>[CH3:1][C:2]([CH3:34])([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6]([C:8]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)=[O:7]
Reactant: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCN(C(=O)OCC(Cl)(Cl)Cl)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester (1.6 g 3 mmol) and zinc (10.5 g 0.16 mol) in a mixture of tetrahydrofurane (25 mL) and 1M aqueous solution of ammonium acetate (13 mL) is stirred overnight at room temperature, diluted with tetrahydrofurane (20 mL) and filtrated over clarcel. The filtrate is diluted with dichloromethane, washed with water dried over magnesium sulfate and concentrated under reduced pressure to give piperidine-3,3-dicarboxylic acid 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester as an oil
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[CH3:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([NH:27][CH3:26])=[O:25])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CN
Product: CNC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Yield: 87 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 and methylamine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (45 mg, Yield 87%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:8]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C1CCNCC1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCN1CCCCC1
Temperature: 55 °C
Yield: 50.4 %

Procedure:
N-decylpiperidine was synthesized by reacting 45.7 g of piperidine with 118.7 g of 1-bromodecane in 237 mL of acetone in the presence of 74 g of potassium carbonate. After refluxing this reaction mixture at 55° C. for 24 hr, it was filtered and acetone was removed from the filtrate to yield 61 g of N-decylpiperidine. N-decylpiperidine (5 g) and 42 g of 1-bromo-3-chloropropane were dissolved in 50 mL of methanol and the reaction mixture was heated to 65° C. for 18 hr. After cooling to room temperature, methanol was removed under reduced pressure. The residue was poured into 2 L of tert-butylmethyl ether with stirring and then the mixture was allowed to stand for 6 hr. The white precipitate was collected by filtered and was dried at 400 C under vacuum for 24 hr yielding 68 g of (3-chloropropyl)decylpiperidinium bromide as a light yellow solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][NH:4][C@H:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1.[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16]>CC(O)C>[CH:1]#[C:2][CH2:3][NH:4][C@H:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1.[C:14]([O-:19])(=[O:18])[C:15]([O-:17])=[O:16]
Reactant: O=C(O)C(=O)O
Agent: C#CCN[C@@H]1CCc2ccccc21
Solvent: CC(C)O
Product: O=C([O-])C(=O)[O-]

Procedure:
60 g rasagiline base were suspended in 885 ml 2-propanol. Then, 32.7 g oxalic acid dissolved in 885 ml 2-propanol were added. The mixture was allowed to stand in a refrigerator overnight, then filtrated and subsequently washed with 100 ml cooled 2-propanol. The residue was dried in a drying cabinet at 45° C. Yield: 87.6 g (93.1% of the theoretical) white crystals; water content (Karl Fischer): about 0.1%; melting point 204° C. (clear, brown melt); TFC: peak at 209.52° C.; [α]D20: +28.9° (2% in ethanol); elemental analysis: C=64.39% (theoretical: 64.36%), H=5.91% (theoretical: 5.79%), N=5.43% (theoretical: 5.36%).
Reaction SMILES: [CH:1]1([C@H:6]2[C:33](=[O:34])[N:32]3[CH2:35][C@@H:29]([CH2:30][C@H:31]3[C:36]([NH:38][C@:39]3([C:44](=[O:52])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[CH2:41][C@H:40]3[CH:42]=[CH2:43])=[O:37])[O:28][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([OH:27])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:53][CH2:54][CH2:55][C@H:10]3[O:9][C:8](=[O:56])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:57](OC(=O)C)(=[O:59])[CH3:58]>N1C=CC=CC=1>[C:57]([O:27][C:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=[C:18]2[O:28][C@H:29]3[CH2:35][N:32]([C:33](=[O:34])[C@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:7][C:8](=[O:56])[O:9][C@@H:10]4[CH2:55][CH2:54][CH2:53][C@H:11]4[CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][C:17]=12)[C@H:31]([C:36](=[O:37])[NH:38][C@:39]1([C:44](=[O:52])[NH:45][S:46]([CH:49]2[CH2:50][CH2:51]2)(=[O:47])=[O:48])[CH2:41][C@H:40]1[CH:42]=[CH2:43])[CH2:30]3)(=[O:59])[CH3:58]
Reactant: CC(=O)OC(C)=O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OC(C)=O)O2)C(=O)NS(=O)(=O)C1CC1
Solvent: c1ccncc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OC(C)=O)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 17) (35 mg) in pyridine (0.44 mL) was added acetic anhydride (42 μl). The reaction mixture was stirred at room temperature until disappearance of the starting material. The reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40% ACN/0.05% TFA water to 100%) afforded the desired product (26 mg) after workup with NaHCO3 and ethyl acetate. LRMS (ES+) m/z 832.8 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5](=[O:20])[C:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:8])[CH3:7])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C(#N)C>[O:20]1[CH:1]=[N:3][N:4]=[C:5]1[C:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:7])[CH3:8]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)NNC=O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NC(=O)OCc1ccccc1)c1nnco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 127.6 %

Procedure:
To a suspension of benzyl 1-(2-formylhydrazinyl)-2-methyl-1-oxopropan-2-ylcarbamate (0.9 g, 3 mmol) and PPh3 (CAN 603-35-0, 1.268 g, 5 mmol) in acetonitrile (20 mL) was added DIPEA (CAN 7087-68-5, 1.249 g, 10 mmol) and hexachloroethane (CAN 67-72-1, 0.991 g, 4 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 4 h. After evaporation of solvents, the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The remaining residue was then purified by column chromatography (silica gel, 30 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (1 g, 30% purity, 36%) as colorless oil containing OPPh3 and PPh3; MS: m/e 262.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:2].F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([N:14]2[CH2:13][CH2:12][N:11]([C:4]3[C:5]([NH2:10])=[N:6][C:7]([NH2:9])=[N:8][C:3]=3[CH2:1][CH3:2])[CH2:16][CH2:15]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: CCc1nc(N)nc(N)c1N1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1nc(N)nc(N)c1N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 140 °C
Yield: 68.3 %

Procedure:
A mixture of 2.2 g (0.010 mole) of 6-ethyl-5-(1-piperazinyl)-2,4-pyrimidinediamine, 1.33 g (0.011 mole) of a 4-fluorobenzonitrile and 1.52 g (0.011 mole) of potassium carbonate in 20 ml of dimethyl sulfoxide was heated under reflux at 140° C. for two hours. The reaction mixture was cooled and poured into 100 ml of ice water. The solid was collected and recrystallized from N,N dimethyl formamide to give 2.21 g of the product as a white solid, mp>310° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(CC)CC)C.[F:18][C:19]([F:23])([F:22])[S:20]Cl>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([S:20][C:19]([F:23])([F:22])[F:18])=[CH:9][N:10]=2)[CH:7]=1
Reactant: FC(F)(F)SCl
Reactant: Clc1cn2ccnc2cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)Sc1cnc2cnc(Cl)cn12

Procedure:
A solution of 6-chloroimidazo[1,2-a]pyrazine (3.07 g, 0.020 mol) in acetonitrile (50 ml) containing 1.01 g (0.010 mol) of triethylamine is treated with a stream of trifluoromethanesulfenyl chloride gas at 25° C. under nitrogen. After 1 hour the solution is flushed with nitrogen, concentrated under vacuum, and the residue partitioned between water-chloroform. The chloroform extract is dried over sodium sulfate, filtered and concentrated under vacuum to give crude 6-chloro-3-trifluoromethylthioimidazo[1,2-a]pyrazine which is purified by fractional sublimation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].BrC1C=C([C:25]([F:28])([F:27])[F:26])C=CC=1O.BrCC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Agent: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(C(F)(F)F)cc1Br

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-bromo-4-(trifluoromethyl)phenol and tert-butyl bromoacetate (Aldrich), the title compound was obtained as a dark orange sticky solid in quantitative yield.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:15]C)=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)#N.[ClH:17]>>[ClH:17].[ClH:17].[CH3:1][NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[NH:15]
Reactant: CNC(=NCCSCc1nccs1)NC#N
Agent: Cl
Product: CNC(=N)NCCSCc1nccs1

Procedure:
(Found: C, 42.3; H, 5.1; N, 27.2; S, 25.3. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1). Hydrolysis of N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine by treating with concentrated hydrochloric acid at 100° for 4 hours gives N-methyl-N'-[2-(2-thiazolylmethylthio)ethyl]guanidine dihydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)[CH3:2].[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[Br:11][C:5]1[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC1=CC(=O)CCC1
Solvent: ClCCl
Product: CCOC1=C(Br)C(=O)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of 3-ethoxy-2-cyclohexenone (70 g, 499 mmol) in CH2Cl2 (300 mL) as a solvent at 0° C. under argon atmosphere was added in portions N-bromosuccinimide (91 g, 511 mmol) over a period of 1 hour. The suspension was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The solvent was removed in vacuo and CH2Cl2 added. The solution was washed twice with a cold saturated NaHCO3 solution and with cold H2O, then dried over anhydrous MgSO4, the solvent removed in vacuo and the resulting solid residue was triturated several times with Et2O, the resulting solid dried in vacuo to afford 101 g (92% yield) of the desired product as white crystals which were characterized as follows:
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])=[CH:10][C:11](=[O:21])[C:12]=1[O:13]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])=[CH:10][C:11](=[O:21])[C:12]=1[OH:13])=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)NC(C)C)n2C)c1
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(O)c(C(=O)NC(C)C)n2C)c1
Yield: 9.8 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (18-04) (20.0 mg, 9.82%, purified by Prep-HPLC) was synthesized as a white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-04) (250.0 mg, 0.518 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [BH4-].[Na+].[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27]C(=O)[CH2:25][CH2:24]4)[CH:21]=[N:20][C:19]=3C3C=CC=CC=3)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:36])(=[O:8])=[O:7])([CH3:5])[CH3:4].[CH3:37][OH:38]>O1CCCC1.O>[CH:3]([S:6]([N:9]1[C:13]2[CH:14]=[C:15]([C:18]3[N:22]([CH:23]4[CH2:24][CH2:25][CH:37]([OH:38])[CH2:27][CH2:28]4)[C:21]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:20][CH:19]=3)[CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH2:36])(=[O:7])=[O:8])([CH3:4])[CH3:5]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCC(=O)CC3)cc21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3cnc(-c4ccccc4)n3C3CCC(O)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Add a solution of sodium borohydride (0.28 g) in methanol (5 mL) to a solution of 1-isopropylsulfonyl-2-amino-6-(1-(cyclohexan-1-on-4-yl)-4(phenyl)-imidazol-5-yl)-benzimidazole (0.35 g, 0.7 mmol) in 10 mL tetrahydrofuran and 10 mL methanol. Stir the reaction mixture for 30 minutes at room temperature, dilute with water (50 mL), and extract with ethyl acetate (2×15 mL). Wash the combined organic extracts with saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure to provide 0.345 g (98%) of the title compound. MS(ES+): m/z=480.2 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[S:11])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:13]([O:15]C)=[O:14].CC([O-])=O.Cl>C(OCC)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[S:11])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=S
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CCC(C(=O)O)N1C(=O)c2ccccc2C1=S
Temperature: 0 °C
Yield: 79.1 %

Procedure:
Compound 208 (350 mg, 1.09 mmol) was stirred with a 1:1 mixture of acetic acid glacial and conc. HCl in a 100° C. oil bath for 2.5 h. Ethyl acetate (100 mL) and ice water (30 mL) were added. The ethyl acetate layer was separated, washed with ice water, dried over Na2SO4 and concentrated. The resulting syrup was crystallized with ether to afford compound 211 as red crystals (253 mg, 79%); mp 157° C.; 1H NMR (DMSO-d6) δ 8.04-7.96 (m, 1H), 7.91-7.74 (m, 3H), 5.43 (dd, J=5.1 Hz, J=9.6 Hz, 1H), 2.42-2.33 (m, 2H), 2.30-2.26 (m, 2H); MS (DEI) m/z 293 (M); HRMS (DEI) calcd. for C13H11NO5S 293.0358 (M+). found 293.0363; Anal. (C13H11NO5S) H, N; C: calcd, 53.24. found, 53.88.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][CH:13]([CH3:20])[C:14]([O:18]C)=[CH:15][CH2:16]O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>C(Cl)Cl>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][CH:13]([CH3:20])[C:14](=[O:18])[CH:15]=[CH2:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: ClCCl
Product: C=CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The alcohol (600 mg) is stirred with 5 ml of 35% HClO4 in CH2Cl2 (5 ml) for about 20 minutes. The solution is then extracted with CH2Cl2 followed by washing, drying and evaporation. The product is then purified by prep. thin layer chromatography to give 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxo-1-pentene, MS m/e 336 (M+).