Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:9][C:8](=O)[CH:7]([CH2:20][OH:21])[CH:6]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:3])[CH3:2].COC[O:33][CH:34]1CC(=O)CC[CH2:35]1>>[C:1]([O:4][CH:5]1[CH:10]([O:11][Si:12]([C:15]([CH3:17])([CH3:16])[CH3:18])([CH3:13])[CH3:14])[CH2:9][C:8]2=[CH:35][C:34](=[O:33])[O:21][CH2:20][CH:7]2[CH:6]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(O[Si](C)(C)C(C)(C)C)CC(=O)C(CO)C1O[Si](C)(C)C(C)(C)C
Reactant: COCOC1CCCC(=O)C1
Product: CC(=O)OC1C(O[Si](C)(C)C(C)(C)C)CC2=CC(=O)OCC2C1O[Si](C)(C)C(C)(C)C
Yield: 34 %

Procedure:
Example 4 was repeated except that 4-acetoxy-3,5-bis(tert-butyldimethylsilyloxy)-2-hydroxymethylcyclohexanone was used instead of 2-hydroxymethyl-3,4-dimethylmethylenedioxy)-5-(methoxymethoxy)cyclohexanone to give 7-acetoxy-6,8-bis(tert-butyldimethylsilyloxy)-1,5,6,7,8,8a-hexahydro-3H-2-benzopyran-3-one having the following property (yield 34%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7][C:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:11]=2[S:10][C:9]=1[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[N+]=[N-].C(S)CCS.C(N(CC)CC)C.[BH4-].[Na+]>ClCCl.C(O)(C)C>[NH2:1][CH2:4][CH2:5][CH2:6][S:7][C:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:11]=2[S:10][C:9]=1[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN=[N+]=[N-])c(Cc3cccc4ccccc34)sc21
Agent: SCCCS
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Reaction time: 8 h
Yield: 45.1 %

Procedure:
5-[(3-Azidopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (656 mg), 1,3-propanedithiol (100 μl) and triethylamine (400 μl) were dissolved in a mixture of dichloromethane (3 ml) and isopropanol (5 ml). Sodium borohydride (78 mg) was added and the mixture was stirred overnight. The solvents were removed by evaporation then dilute hydrochloric acid was added dropwise until effervescence ceased. The solution was made alkaline with aqueous sodium hydroxide and then extracted with dichloromethane (four times). The extracts were dried, filtered and evaporated. Purification by HPLC (ethanol:dichloromethane 5-40:95-60) followed by trituration with ether-cyclohexane gave the title compound (280 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:24])=[C:10]([N+:25]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O>P(OCC)(OCC)OCC>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:9]=[C:10]2[C:11]([CH:14]=[C:15]([C:16]3[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:24])[NH:25]2)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(Cl)c1/C=C/c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Solvent: O
Product: COc1cccc(Cl)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A solution of {4-[(E)-2-(2-chloro-6-methoxy-phenyl)-vinyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (240 mg, 0.59 mmol) in triethyl phosphite (5.0 ml) was refluxed for 3 h. The reaction mixture was cooled to 25° C., and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded [2-(2-chloro-6-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (140 mg, 63%) as a white solid. MH+ 373.0.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=1.O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:10][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH:19]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
Sodium hydride (63%, 25 g, 656 mmol) was added to a solution of 4-methoxybenzyl alcohol (90.3 g, 654 mmol) and tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (US200216506 A1, 156 g, 544 mmol) in DMF (1.4 L) at room temperature, and the mixture was stirred at 80° C. for four hours. After leaving to cool, water (1.5 L) was added to the reaction mixture. The precipitated solid was collected by filtration to obtain the title compound (209 g, 99%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:13]>>[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:18])[CH3:13]
Reactant: Cc1cccc(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOc1ccccc1C(=O)Nc1c(C)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-methylbenzamide (Chem. Pharm. Bull., 1988, 36, 2955) and 2-ethoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as colourless crystals (71%), m.p. 197-200° C.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[Si]([O:35][CH2:36][C:37]1[CH:38]=[C:39]([C:43]([C:45]2[N:46]=[CH:47][N:48]3[CH:52]=[C:51]([C:53]4[C@H:54]([CH3:77])[C@@H:55]5[C@@H:72]([C@H:73]([OH:75])[CH3:74])[C:71](=[O:76])[N:56]5[C:57]=4[C:58]([O:60][CH2:61][C:62]4[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=4)=[O:59])[S:50][C:49]=23)=[O:44])[CH:40]=[N:41][CH:42]=1)(C(C)(C)C)(C)C.O>C1COCC1>[OH:75][C@@H:73]([C@H:72]1[C:71](=[O:76])[N:56]2[C:57]([C:58]([O:60][CH2:61][C:62]3[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=3)=[O:59])=[C:53]([C:51]3[S:50][C:49]4=[C:45]([C:43]([C:39]5[CH:40]=[N:41][CH:42]=[C:37]([CH2:36][OH:35])[CH:38]=5)=[O:44])[N:46]=[CH:47][N:48]4[CH:52]=3)[C@H:54]([CH3:77])[C@H:55]12)[CH3:74]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(CO[Si](C)(C)C(C)(C)C)c5)c4s3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(CO)c5)c4s3)[C@H](C)[C@H]12
Reaction time: 6 h
Yield: 91.9 %

Procedure:
Under ice cooling, 0.092 ml of acetic acid and 0.799 ml of a 1 M tetra-n-butylammonium fluoride/THF solution were added to a solution of 563 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-[5-(t-butyldimethylsilyloxymethyl)pyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 8 ml of THF, and the mixture was stirred for 6 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation. The residue was purified by column chromatography (dichloromethane:methanol=1:1) on Sephadex LH-20 to give 435 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[5-(hydroxymethyl)pyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:14][C:15]1[C:16]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:17][C:18]2[O:22][C:21]([CH2:24][NH2:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[C:27]([CH3:30])([CH3:29])[CH3:28])(=O)C.O>C1(C)C=CC=CC=1>[NH2:25][CH2:24][C:21]1([CH3:23])[CH2:20][C:19]2[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:15]([OH:14])[C:16]([C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:17][C:18]=2[O:22]1
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CN)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(CN)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.9 %

Procedure:
Under a nitrogen atmosphere, 13.2 ml of 1M diisobutyl aluminum hydride solution in toluene was added dropwise to a solution of 1.0 g of 5-acetoxy-2-aminomethyl-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran in 30 ml of toluene at room temperature. After stirring at room temperature for 14 hours, the mixture was combined with water and extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by recrystallization from a mixed solvent of ethyl acetate and hexane to give 0.62 g of 2-aminomethyl-4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran as a white crystal (yield 71%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[NH:21][N:20]=2)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=1)[C:41]([O:43][CH3:44])=[O:42]>CN(C=O)C.C(Cl)Cl.O>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[N:21]([CH2:37][C:38]3[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=3)[C:41]([O:43][CH3:44])=[O:42])[N:20]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1cccc2[nH]nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(Cn2nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c3c(OC)cccc32)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (1 g, 2.11 mmol) in DMF (10 mL) was treated at ambient temperature with potassium carbonate (0.583 g, 4.22 mmol) and methyl 3-(bromomethyl)benzoate (Alfa Aesar) (0.580 g, 2.53 mmol). The resulting mixture was stirred at 50° C. for 2 h and the LCMS then showed product as the major peak. The mixture was diluted with DCM (20 mL) and of water (20 mL). The organic phase was separated and the aqueous layer was further extracted with DCM (20 mL). The combined organic solutions were washed with brine (30 mL), dried over an hydrophobic frit, and concentrated under reduced pressure. The residue was loaded in dichloromethane to a silica 100 g cartridge and purified by chromatography on Flashmaster II using a 0-100% gradient B in A, A beeing neat DCM and B being a 5% EtOAC in DCM solution over 40 min. and then further purified on a second cartridge silica 70 g using a 0-100% gradient B in A, A beeing neat DCM and B being a 5% EtOAC in DCM solution over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (571 mg, 44%) as a gum. LCMS (System A) RT=1.60 min, ES+ve m/z 639/641 (M+NH4)+.
Reaction SMILES: C([O:5][C:6](=[O:22])[C@H:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C@H:8]([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:16][O:15][C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@@H:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:6]([OH:22])=[O:5]
Reactant: CCCCCC[C@@H](OC)[C@@H](CCCCC)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC[C@@H](OC)[C@@H](CCCCC)C(=O)O
Temperature: 0 °C
Yield: 92.3 %

Procedure:
The (2R,3R)-3-methoxy-2-pentylnonanoic acid t-butyl ester (450 mg, 1.43 mmol) obtained in Production Example C-9 was dissolved in anhydrous dichloromethane (10 ml), then cooled to 0° C. While the obtained solution was stirred, trimethylsilyl triflate (162 mg, 729 μmol) was added dropwise thereto. After a five-minute stirring, the solution was cooled to room temperature. After the reaction of 30 minutes, an aqueous saturated sodium bicarbonate solution was added thereto to be washed. The resulting organic layer was dried with anhydrous magnesium sulfate, filtered, and condensed. The obtained residue was purified by column chromatography (silica gel: 15 g, n-hexane/ethyl acetate=3/1) to produce the target compound (341 mg, 92%).
Reaction SMILES: Cl.[CH:2]1([C:5]([NH:7][C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:6])[CH2:4][CH2:3]1.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:2]1([C:5]([NH:7][C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][N:11]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:12][CH2:13]2)=[O:6])[CH2:3][CH2:4]1
Reactant: O=C(NC1(c2ccccc2)CCNCC1)C1CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(c2ccccc2)CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C1CC1
Yield: 102.1 %

Procedure:
A mixture of 0.565 g of 4-(cyclopropylcarbonylamino)-4-phenylpiperidine hydrochloride in 50 ml of DCM is cooled to +5° C., 0.565 g of trityl chloride is added followed by 0.7 ml of triethylamine and the mixture is kept stirring while allowing the temperature to rise to RT. The reaction mixture is washed with water, the organic phase dried over MgSO4 and the solvent evaporated under vacuum. 1 g of the expected product is obtained after crystallization from ether.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH2:14][CH3:15])[CH3:13])[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[N:3]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1.[H-].[Na+]>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:11]=[C:10]([N:12]([CH2:14][CH3:15])[CH3:13])[C:9]4[CH2:8][CH2:7][CH2:6][CH:5]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:4]=4[N:3]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CCN(C)c1nc(Cl)nc2c1CCCC2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCCC2c1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 33.8 %

Procedure:
To a solution of 2-chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (42.9 mg, 0.142 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (31.8 mg, 0.142 mmol) in THF (2 mL) was added 60% suspension of sodium hydride in mineral oil (6.82 mg, 0.284 mmol). The reaction mixture was heated with stirring in a capped vial at 80° C. for 1.5 h. The reaction mixture was carefully partitioned between an aqueous solution of ammonium chloride and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by reverse-phase preparative HPLC to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine (31.6 mg, 0.048 mmol, 33.5% yield) as brown oil. LC-MS (M+H)+=489.2. 1H NMR (500 MHz, CDCl3) δ ppm 11.50 (1H, br s), 7.74 (1H, d, J=1.2 Hz), 7.39 (1H, dd, J=8.5, 2.1 Hz), 7.29 (2H, dd, J=4.9, 2.7 Hz), 7.21-7.27 (2H, m), 7.12-7.19 (3H, m), 7.07 (1H, d, J=1.5 Hz), 4.20 (1H, t, J=7.0 Hz), 3.80 (3H, s), 3.68-3.78 (2H, m, J=13.8, 7.0, 7.0, 7.0, 7.0 Hz), 3.31 (3H, s), 2.64-2.82 (2H, m), 2.27 (1H, ddd, J=13.3, 7.5, 5.2 Hz), 1.88-1.99 (1H, m), 1.74-1.85 (1H, m), 1.54-1.67 (1H, m), 1.34 (3H, t, J=7.0 Hz).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][C:18]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])([CH2:19][CH2:20]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]>CO.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][C:18]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])([CH2:19][CH2:20]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=CC(=O)O)(CC3)C4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CCC(=O)O)(CC3)C4)nc2n(CCC)c1=O
Yield: 81.1 %

Procedure:
A suspension of 3-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]oct-1-yl]-acrylic acid methyl ester (Example 12) (0.58 mmol, 0.25 g) and 10% Pd/C (50% H2O, 0.029 mmol, 0.062 g) in MeOH (20 ml) was hydrogenated at 40 psi overnight. The completed reaction was filtered through Celite, rinsing with MeOH. Evaporation provided the desired product (0.196 g, 79%) as an oil. MS (ES+) 431.18 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C=Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1cccc(C=Cc2c[nH]cn2)c1

Procedure:
A mixture of 11 g of the product obtained in Step 3, 6 ml of concentrated hydrochloric acid and 150 ml of methanol is heated at reflux for 2 hours. The solvent is concentrated and the residue is taken up in an isopropanol/diethyl ether mixture. The expected product is obtained by filtering off the precipitate that has formed.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([S:17][CH3:18])=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]=12)=[O:5])C.O[Li].O>C(O)C.C1COCC1.O.OS([O-])(=O)=O.[K+]>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][C:10]2=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]([S:17][CH3:18])=[C:9]2[CH2:14]1
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C)(C)C2
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CSc1sc(C(=O)O)c2c1CC(C)(C)CC2
Yield: 132.3 %

Procedure:
A solution of 5,5-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester (458 mg, 1.61 mmol) and LiOH.H2O (696 mg, 16.6 mmol) in ethanol (5 mL), THF (3 mL) and water (0.6 mL) is stirred at rt overnight. The mixture is diluted with aq. KHSO4 and extracted with DCM. The organic extract is dried over Na2SO4, filtered and the solvent is removed in vacuo to give 5,5-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (546 mg) as a beige solid; LC-MS: tR=1.00 min, [M+1]=257.6; 1H NMR (CDCl3): δ 2.98 (t, J=7.0 Hz, 2H), 2.49 (s, 3H), 2.34 (s, 2H), 1.55 (t, J=7.0 Hz, 2H), 0.98 (s, 6H).
Reaction SMILES: NC1C(=O)NC=CC=1C(F)(F)F.[F:13][C:14]([F:22])([F:21])[C:15](=O)[CH2:16][C:17](=O)[CH3:18].[N+:23]([CH2:26][C:27]([NH2:29])=[O:28])([O-:25])=[O:24]>C(NCC)C>[OH:28][C:27]1[C:26]([N+:23]([O-:25])=[O:24])=[C:15]([C:14]([F:22])([F:21])[F:13])[CH:16]=[C:17]([CH3:18])[N:29]=1
Reactant: NC(=O)C[N+](=O)[O-]
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: Nc1c(C(F)(F)F)cc[nH]c1=O
Solvent: CCNCC
Product: Cc1cc(C(F)(F)F)c([N+](=O)[O-])c(O)n1

Procedure:
A method for preparing compounds which are derivatives of 3-amino-4-trifluoromethyl-2-pyridinone is illustrated in Scheme 3. In Step A, 1,1,1, trifluoro-2,4-pentanedione is condensed with nitroacetamide in ethanolic diethylamine to give 2-hydroxy-6-methyl-3-nitro-4-trifluoromethylpyridine. This is alkylated in Step B with an acetate equivalent such as t-butyl bromoacetate in THF using sodium hydride as a base and the nitro group is reduced in Step C by hydrogenation using a catalyst such as palladium on carbon. The t-butyl group is removed in Step D by a strong acid such as HCl and the resulting carboxylic acid is coupled to ethyl-2-aminomethyl-4-chlorophenoxyacetamide in Step E to give the final product.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([N:22]([CH:30]([CH3:32])[CH3:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][C@H:17]1[CH2:33][OH:34])=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH2:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([N:22]([CH:30]([CH3:31])[CH3:32])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:18][C@H:17]1[CH2:33][OH:34])=[O:14]
Reactant: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CNC(=O)OCc2ccccc2)[C@H](CO)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CN)[C@H](CO)C1

Procedure:
A solution of tert-butyl(1R,3R,4S)-4-(2-Benzyloxycarbonylamino-acetylamino)-3-(hydroxymethyl)cyclohexyl(isopropyl)carbamate (2.2 g, 0.0046 mol), in 30 mL of MeOH was treated with 1 g of 10% Pd/C and hydrogenated overnight at 55 psi. The mixture was filtered through Celite and concentrated on a rotary evaporator to give tert-butyl(1R,3R,4S)-4-(2-aminoacetamido)-3-(hydroxymethyl)cyclohexyl-(isopropyl)carbamate as a white solid. This was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[CH:10][C:3]=12.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Cl[C:42]1[N:47]=[C:46]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][C@H:49]2[CH3:54])[CH:45]=[C:44]([C:55]2([S:58]([CH3:61])(=[NH:60])=[O:59])[CH2:57][CH2:56]2)[N:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:54][C@H:49]1[N:48]([C:46]2[CH:45]=[C:44]([C:55]3([S:58]([CH3:61])(=[NH:60])=[O:59])[CH2:57][CH2:56]3)[N:43]=[C:42]([C:2]3[CH:7]=[N:6][CH:5]=[C:4]4[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[CH:10][C:3]=34)[N:47]=2)[CH2:53][CH2:52][O:51][CH2:50]1
Reactant: C[C@@H]1COCCN1c1cc(C2(S(C)(=N)=O)CC2)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)cncc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1c1cc(C2(S(C)(=N)=O)CC2)nc(-c2cncc3c2ccn3C(=O)OC(C)(C)C)n1
Yield: 46.1 %

Procedure:
1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.906 g, 1.25 mmol) was added to tert-butyl 4-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.24 g, 4.17 mmol), potassium acetate (2.87 g, 29.21 mmol) and bis(pinacolato)diboron (4.73 g, 18.63 mmol) in dioxane (100 ml) under nitrogen. The resulting solution was stirred at reflux for 3 days to afford an approximate 2:1 mixture of boc to de-boc product. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (0.017 g, 0.02 mmol), (3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (0.318 g, 0.96 mmol), 2M aqueous sodium carbonate solution (0.577 mL, 1.15 mmol) under nitrogen. The reaction mixture was stirred at 90° C. for 6 hours. The reaction mixture was concentrated, diluted with EtOAc (400 ml), and then washed sequentially with water (300 ml) and saturated brine (75 ml). The organic layer was dried over MgSO4, filtered and then evaporated directly onto silica (30 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(4-((R)-3-methylmorpholino)-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.227 g, 46%); 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40-1.61 (3H, m), 1.68 (9H, s), 1.76 (1H, dd), 3.09 (3H, d), 3.24 (1H, m), 3.52 (1H, t), 3.67 (1H, dd), 3.79 (2H, d), 4.00 (1H, dd), 4.19 (1H, s), 4.56 (1H, s), 7.00 (1H, d), 7.57 (1H, d), 8.00 (1H, d), 9.25 (1H, s), 9.37 (1H, s); m/z: (ES+) MH+, 513.19.