Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([OH:8])[CH2:3]1.[OH-].[Na+].CS(O[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:27]2[CH2:30][CH:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][CH:40]=4)=[C:33]([O:47][CH3:48])[CH:32]=3)[CH2:28]2)=[O:26])[CH:20]=1)(=O)=O.O>C(O)CC>[OH:8][C@@H:4]1[C@@H:5]([OH:7])[CH2:6][N:2]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:27]3[CH2:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]5[CH:40]=[CH:41][C:42]([CH2:45][CH3:46])=[CH:43][CH:44]=5)=[C:33]([O:47][CH3:48])[CH:32]=4)[CH2:30]3)=[O:26])[CH:20]=2)[CH2:3]1
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCN5C[C@H](O)[C@@H](O)C5)ccn4)C3)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
a solution of (3S,4S)-pyrrolidine-3,4-diol monohydrochloride (0.14 g) in 1-propanol (3.0 mL) was added aqueous 4 N NaOH (0.25 mL). The mixture was stirred at RT for 1 hr. To the mixture was added 2-(2-{3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-yloxy)ethyl methanesulfonate (0.1 g) prepared in Example 6 (1). The reaction mixture was stirred at 100° C. for 5 hr. Water was added to the reaction mixture. The precipitated solid was collected on a filter and dried to give the title compound (0.05 g, 50%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
34.1 g (0.12 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride, dissolved in 300 ml of dichloromethane, are added dropwise at 15 to 20° C. to a solution of 22.43 ml (0.11 mol) of 4-amino-1-benzyl-piperidine and 42.97 ml (0.31 mol) of triethylamine in 600 ml of dichloromethane. The mixture is stirred for 14 hours at ambient temperature. The reaction solution is diluted with 300 ml of dichloromethane and extracted with a mixture of 1N sodium hydrogen carbonate solution and 1N sodium hydroxide solution. The organic phase is dried over sodium sulphate and the solvent is eliminated. The residue is recrystallised from 650 ml ethanol.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H][H]>[Ni].O1CCCC1>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N)cc2C)cc1

Procedure:
30.6g (0.6 mole) of 4-(N-p-toluenesulfonyl)amino-3-methyl-nitrobenzene 1g of fresh-developed Raney nickel and 60ml of tetrahydrofuran were charged into an autoclave and the autoclave was pressurized to 60kg/cm2 with hydrogen. The reaction was carried out at 50° to 100° C while stirring. After completion of the reaction, the Raney nickel was removed from the reaction solution and the tetrahydrofuran was distilled out to obtain brown 4-(N-p-toluenesulfonyl)amino-3-methylaniline. The product was recrystallized from ethyl acetate to obtain 24g of yellow-brown crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].ON1C2C=CC=CC=2N=N1.[C:29]([NH:39][C@H:40]([C:45](O)=[O:46])[CH2:41][CH2:42][S:43][CH3:44])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH2:32]([O:31][C:29]([NH:39][C@@H:40]([CH2:41][CH2:42][S:43][CH3:44])[C:45]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:46])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CO[C@@H]1CC[C@H](N)[C@H](CNC(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CO[C@@H]1CC[C@H](NC(=O)[C@H](CCSC)NC(=O)OCc2ccccc2)[C@H](CNC(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A sample of tert-butyl ((1S,2S,5R)-2-amino-5-methoxycyclohexyl)methylcarbamate (2.53 g, 9.79 mmol) was dissolved in CH2Cl2 (50 ml) at room temperature. The solution was charged sequentially with 1-hydroxybenzotriazole (1.456 g, 10.77 mmol), N-carbobenzyloxy-L-methionine (4.16 g, 14.69 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.440 g, 12.73 mmol). The reaction mixture was stirred overnight. It was diluted with EtOAc and washed with saturated Na2CO3, followed by brine. The solution was dried (MgSO4), filtered, and concentrated in vacuo to yield tert-butyl ((1S,2S,5R)-2-((S)-2-benzyloxycarbonylamino-4-(methylthio)butanamido)-5-methoxycyclohexyl)methylcarbamate as a colorless sticky solid. LC/MS found [M+H]+=524.31.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:6]([Br:5])=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][C:12]=1[Br:15]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(OCCBr)c(Br)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
1,2-Dibromoethane (62 mL, 0.72 moles) was added to a mixture of 3,5-dibromo-4-hydroxybenzaldehyde (10 g, 36 mmoles) and potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred vigorously at 70° C. for 16 hours. After cooling, the mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL). Water (200 mL) was added to the aqueous phase and this was extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chloride (3×150 mL), dried over MgSO4 and evaporated in vacuo. The residue was dissolved in refluxing 96% ethanol (60 mL). Water (15 mL) was added and after cooling, filtration, washing with 60% ethanol and drying 10.7 g (77%) of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde was isolated in two crops. M.p. 84-85° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1=O>[N:17]1[CH:18]=[CH:19][CH:14]=[CH:15][C:16]=1[C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1(c2ccccn2)CCNCC1

Procedure:
Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 μL) and the resulting solution heated at 100° for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL) and washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2 Cl2) to afford ethyl 4-(pyridyl)piperidin-4-yl-carboxylate as a crystalline solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[NH:4][C:5](=[O:10])[NH:6][C:7]=1[CH2:8][CH3:9].[F-].[K+].[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:8]([C:7]1[NH:6][C:5](=[O:10])[NH:4][C:3](=[O:11])[C:2]=1[N:24]1[CH2:25][CH2:26][N:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH3:9]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCc1[nH]c(=O)[nH]c(=O)c1Br
Agent: [F-]
Agent: [K+]
Product: CCc1[nH]c(=O)[nH]c(=O)c1N1CCN(Cc2ccccc2)CC1
Temperature: 140 °C

Procedure:
A mixture of 57.0 g (0.260 mole) of 5-bromo-6-ethyl-2,4(1H,3H)pyrimidinedione and 26.6 g (0.286 mole) of anhydrous potassium fluoride in 176 ml (1 mole) of 1-benzylpiperazine was heated under reflux at 140° C. for four hours and cooled. The reaction mixture was poured into 1000 ml of ice water. The solid was collected and washed with water. Recrystallization from N,N dimethylformamide and drying in vacuo at 59° C. for 16 hours gave the product as an off-white solid; mp 255°-256° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=[C:11]2[CH2:10][N+:9]=1[O-].[C:27]([O:30]C(=O)C)(=[O:29])[CH3:28]>>[C:27]([O:30][CH:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[N:22]=[C:11]12)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C[N+]([O-])=C2c1ccccc1Cl
Product: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(OC(C)=O)N=C2c1ccccc1Cl

Procedure:
A mixture of 1.2 g. of 6--(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxamide-5-oxide and 20 ml. of acetic anhydride is heated at 90° to 95° C. for 50 minutes, and then the solvent is evaporated. The residue is washed with ether to give 4-acetoxy-6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]diazepine-2-carboxamide as crystals. Recrystallization from ethyl acetate gives colorless prisms melting at 168° to 170° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:17])=C([CH:9]=[C:10]([Br:16])[C:11]=1[S:12][CH2:13][CH:14]=[CH2:15])C#N)[CH:2]=[CH2:3].[OH-].[Na+].Cl.C[CH2:22][O:23][C:24]([CH3:26])=[O:25]>CCO.O>[Br:16][C:10]1[C:11]([S:12][CH:13]=[CH:14][CH3:15])=[C:4]([CH:1]=[CH:2][CH3:3])[C:5]([Cl:17])=[C:26]([CH:9]=1)[C:24]([O:23][CH3:22])=[O:25]
Reactant: C=CCSc1c(Br)cc(C#N)c(Cl)c1CC=C
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC=CSc1c(Br)cc(C(=O)OC)c(Cl)c1C=CC
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-allyl-4-(allylthio)-5-bromo-2-chlorobenzonitrile 94 (1.1 g, 3.35 mmol) in a mixture of EtOH (90 mL) and H2O (10 mL) was added NaOH (545 mg, 13.4 mmol). The reaction mixture was warmed up to 100° C., and stirred overnight. After reaction complete, the resulting solution was cooled down to room temperature. 1N HCl solution was used for acidify reaction solution, and normal work-up with EtOAc was proceeded. Removal of volatile solvent was preceded by drying with MgSO4. Without further purification, crude acid was used for next step. The crude acid was dissolved in MeOH (50 mL), treated with SOCl2 (1 mL) provisionally. The reaction mixture was refluxed overnight and resulting solution was cooled down to room temperature and evaporated in vacuo. The residue was purified by silica gel chromatography to afford the desired product (710 mg, 63% overall yield) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([OH:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:23][C:22]([F:25])([F:24])[S:19]([O:18]/[C:11](=[C:10]1/[CH:2]([CH:1]([CH3:7])[CH3:6])[O:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]/1)/[CH3:12])(=[O:20])=[O:21]
Reactant: CC#CCCC(O)c1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(OS(=O)(=O)C(F)(F)F)=C1/CCC(c2ccccc2)OC1C(C)C
Reaction time: 1 h
Yield: 75 %

Procedure:
In dichloromethane (3.0 mL) were dissolved 1-phenylhex-4-yn-1-ol (0.28 mmol) and isobudylaldehyde (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. At the same temperature, the reaction solution was stirred for 1 hour, followed by slow temperature elevation to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 75%).
Reaction SMILES: C([N:8]([CH2:22][C:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[N:24]O)[C@H:9]([CH2:14][CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10](OC)=[O:11])C1C=CC=CC=1.C(N(CC(C1C=C(F)C=C(F)C=1)=NO)[C@@H](CC1CCCCCC1)C(OC)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH:15]1([CH2:14][C@H:9]2[NH:8][CH2:22][CH:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[NH:24][C:10]2=[O:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)[C@@H](CC1CCCCCC1)N(CC(=NO)c1cc(F)cc(F)c1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)[C@H](CC1CCCCCC1)N(CC(=NO)c1cc(F)cc(F)c1)Cc1ccccc1
Solvent: CO
Product: O=C1NC(c2cc(F)cc(F)c2)CN[C@@H]1CC1CCCCCC1

Procedure:
Under a hydrogen atmosphere 5.5 g (12.0 mmol) methyl (R)-2-(benzyl-{2-(3,5-difluoro-phenyl)-2-[hydroxyimino]-ethyl}-amino)-3-cycloheptyl-propionate (this compound may be prepared analogously to the synthesis of methyl (S)-2-(benzyl-{2-(3,5-difluoro-phenyl)-2-[hydroxyimino]-ethyl}-amino)-3-cycloheptyl-propionate described herein using the corresponding (R)-configured starting component) and 0.70 g palladium on charcoal (10%) were hydrogenated in 30 ml of methanol for 3 days at 50° C. to 60° C. and 3 bar hydrogen pressure. After elimination of the catalyst the filtrate was concentrated by rotary evaporation. Purification was carried out by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][C@@H:24]4[CH2:28][CH2:29][CH2:30][C@@H:23]34)[N:19]([CH2:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]3)[C:4]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[N:6][C:7]=1[C:8](=[N:10][OH:11])[NH2:9].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[C:3]2[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][C@@H:24]4[CH2:28][CH2:29][CH2:30][C@@H:23]34)[N:19]([CH2:31][C@H:32]3[CH2:33][CH2:34][C@H:35]([CH3:38])[CH2:36][CH2:37]3)[C:4]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[N:6][C:7]=1[C:8]1[NH:9][C:39](=[O:40])[O:11][N:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (33.3 mg, 0.06 mmol) in acetonitrile (2 mL) were added 1,1′-carbonyldiimidazole (19.3 mg, 0.119 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.036 mL, 0.238 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The residue was purified by mass triggered reverse phase HPLC (C-18) eluting with acetonitrile/water+0.1% TFA to afford 3-{7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt). MS ESI calc'd for C28H31Cl2N7O3 [M+H]+=584. found=584. 1H NMR (600 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.92 (d, J=1.2 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.46 (m, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.77-3.86 (m, 2H), 3.56-3.62 (m, 2H), 3.39 (m, 1H), 3.05 (m, 1H), 2.87 (m, 1H), 2.31 (m, 1H), 1.86 (m, 1H), 1.71 (m, 1H), 1.51-1.64 (m, 2H), 1.32-1.41 (m, 2H), 1.12 (m, 1H), 1.04 (m, 1H), 0.81 (m, 1H), 0.65-0.74 (m, 6H), 0.46 (m, 1H), 0.30-0.42 (m, 2H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11](/[CH:15]=[CH:16]/[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:10]([CH3:30])[CH:9]=1)=[O:7])CCC.O1CCCC1>C(O)C.[OH-].[Na+]>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17](/[CH:16]=[CH:15]/[C:11]2[C:10]([CH3:30])=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:13][C:12]=2[CH3:14])[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCCOC(=O)c1cc(C)c(/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)O)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99 %

Procedure:
To a solution of 209 mg of tert-butyl 4-{(E)-2-[4-(butoxycarbonyl)-2,6-dimethylphenyl]vinyl}piperidine-1-carboxylate in 5 ml of ethanol, 1.5 ml of 1N aqueous sodium hydroxide solution was added, followed by stirring at ambient temperature for 3.5 hours. After 1 ml of tetrahydrofuran was added to the reaction mixture, the mixture was stirred at 50° C. overnight. The solvent was evaporated under reduced pressure, water and 1.6 ml of 1N hydrochloric acid were added thereto. The formed precipitates were collected by filtration and dried to give 179 mg of 4-{(E)-2-[1-(tert-butoxycarbonyl)piperidin-4-yl]vinyl}-3,5-dimethylbenzoic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](O)=O.S(O)(O)(=O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[NH:15].C(=O)([O-])O.[Na+]>ClC1C=CC(Cl)=CC=1Cl>[CH3:1][O:2][CH2:3][C:4]1[NH:15][C:14]([NH2:16])=[N:13][N:12]=1
Reactant: N=C(N)NN
Reactant: COCC(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: COCc1nnc(N)[nH]1
Temperature: 200 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A mixture of methoxyacetic acid (15 g), aminoguanidine sulfate (21 g) and 1,2,4-trichlorobenzene (20 mL) was stirred at 200° C. for 24 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with n-butanol. The obtained n-butanol layer was concentrated, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (15 g, 75%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN[CH2:30][CH2:31]NC.C([Al](CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13](=[O:14])[CH2:30][CH3:31])[CH:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Reactant: CNCCNC
Agent: CC[Al](CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure O, 6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid ethyl ester (Compound 25, 94 mg, 0.25 mmol) in toluene (3 ml), N,N′-dimethylethylenediamine (DMEDA, 25 mg, 0.28 mmol) and triethylaluminum (0.7 ml, 0.76 mmol, 1 M in hexane) were reacted to produce the title compound as a oil.
Reaction SMILES: [CH2:1]([N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:18]([NH2:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:11]1[C:12](=[O:17])[CH2:13][CH:14]([NH:28][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN1C(=O)C=CC1=O
Reactant: CCCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCNC1CC(=O)N(CCCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-decyl maleimide (0.01 M) prepared as described in Example 11 above, decylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]1.O>CN1C(=O)N(C)CCC1>[OH:15][C@@H:12]1[CH2:13][CH2:14][N:10]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:11]1
Reactant: O[C@@H]1CCNC1
Reactant: N#Cc1cccc(F)c1
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: N#Cc1cccc(N2CC[C@@H](O)C2)c1
Temperature: 180 °C
Yield: 62.7 %

Procedure:
3-Fluorobenzonitrile (0.385 g, 3.18 mmol) and (3R)-pyrrolidin-3-ol (0.278 g, 3.19 mmol) were dissolved in DMPU (3 mL). The resulting mixture was subjected to microwave heating at 180° C. for 5 h. Water was added and the mixture extracted with ether. The organic layer washed with water, dried with MgSO4, filtered and concentrated. Purification on a 10 g Isolute Flash Si column (heptane/EtOAc 2:1→1:1) gave 0.375 g (63%) of the title compound. 1H NMR (400 MHz, MeOH-d4) δ 7.22 (dd, 1H, J=8.5, 7.5 Hz), 6.82 (d, 1H, J=7.5 Hz), 6.72 (dd, 1H, J=8.5, 2.2 Hz), 6.69 (bs, 1H), 4.48 (m, 1H), 3.42-3.33 (m, 2H), 3.24 (ddd, 1H, J=8.8, 8.8, 3.4 Hz), 3.13 (bd, 1H, J=10.5 Hz), 2.14-1.94 (m, 2H). 13C NMR (MeOH-d4) δ 149.2, 130.9, 120.6, 119.5, 117.0, 114.9, 113.4, 71.4, 56.7, 46.5, 34.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O-])([O-])=[O:14].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:14][CH3:13])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 50 °C
Yield: 95 %

Procedure:
To a solution of 2.45 g (14.0 mmol) of 1,3,5-trifluoro-2-nitrobenzene in acetone are successively added 2.9 g (21.0 mmol) of K2CO3 powder and 3.5 mL (56.0 mmol) of methyl iodide. The reaction mixture is heated at 50°C. for 2 hours and then filtered and evaporated to dryness. The residue is taken up in ethyl acetate and washed with water and with saturated aqueous NaCl solution. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. 2.52 g of the expected product are recovered in the form of a yellow solid, which is used as obtained in the following step. Yield=95%.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:18]([F:21])([F:20])[F:19])=[O:17])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([S:16]([C:18]([F:21])([F:19])[F:20])=[O:17])=[CH:14][CH:15]=3)=[O:8])[CH:22]=2)[CH:33]=[N:32][CH:31]=1
Reactant: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using 5-bromo-6-((R)-3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)sulfinyl)phenyl)nicotinamide (Stage 222.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=4.46 min, UPLC-MS (Condition 3) tR=0.87 min, m/z=495.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.78 (m, 1H) 1.79-1.88 (m, 1H) 2.88 (d, J=1.00 Hz, 1H) 3.22 (m, J=4.70 Hz, 2H) 3.34-3.44 (m, 1H) 4.14-4.23 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.86 (d, J=8.99 Hz, 3H) 8.01-8.14 (m, 3H) 8.50 (s, 1H) 8.59 (d, J=2.74 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.40 (s, 1H).