Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C=C(OCC[NH:11][C:12](N)=[NH:13])C2C=CC=CC=2O1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33](=[O:41])[CH:32]=1>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[O:41]=[C:33]1[CH:32]=[C:31]([O:30][CH2:29][CH2:28][CH2:27][NH:26][C:12]([NH2:13])=[NH:11])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34]1
Reactant: N=C(N)NCCOc1cc(=O)oc2ccccc12
Reactant: NCCCOc1cc(=O)oc2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCOc1cc(=O)oc2ccccc12

Procedure:
Is prepared according to the procedure for N-[2-(2-oxo-2H-1-benzopyran-4-yloxy)-ethyl]-guanidine from the trifluoroacetic acid salt of 4-(3-amino-propoxy)-1-benzopyran-2-one to afford the title compound as the trifluoroacetic acid salt after HPLC purification (40.0 mg, 35%). 1H NMR (DMSO-d6, 300 MHz) δ 7.88 (1H, dd, J=1.5, 8 Hz), 7.67 (2H, m), 7.39 (2H, m), 7.15 (3H, br s), 5.92 (1H, s ), 4.26 (2H, t, J=6 Hz), 3.32 (2H, buried under solvent peak), 2.03 (2H, m); MS (ESI, Pos.) calcd for C13H15N3O3 m/z [M+H]=262.1, found 262.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:3]1.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[F:38][C:37]([F:40])([F:39])[CH2:36][NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:3]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](N)C3)ccnc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](NCC(F)(F)F)C3)ccnc21
Temperature: 40 °C

Procedure:
A mixture of (S)-4-(3-aminopyrrolidin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (131 mg, 0.32 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (490 mg, 2.1 mmol), and N,N-diisopropylethylamine (365 uL, 2.1 mmol) in methylene chloride (15 mL) was heated at 40° C. for 4 hours. The cooled reaction mixture was diluted with water (20 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-20% methanol in methylene chloride) to afford the title compound as an oil, which was used in the next step without any further purification (156 mg, 100%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])(C)(C)C.[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:27]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:28])[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCCN)C1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCCNC(=O)C2CCCCC2)C1

Procedure:
5-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 1 using cyclohexanecarbonyl chloride (0.52 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.70 g) to give 4-amino-5-chloro-N-((3R)-1-(5-cyclohexanecarbonylaminopentyl)pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH:25]=[CH2:26])[NH:20]2)=[CH:15][CH:14]=1.[CH:27]([CH2:29][C:30](O)=[O:31])=[CH2:28].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C@H:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH:25]=[CH2:26])[N:20]2[C:30](=[O:31])[CH2:29][CH:27]=[CH2:28])=[CH:17][CH:18]=1
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(OC)cc2)N1
Reactant: C=CCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Diethyl cyanophosphonate (0.67 mL) was added to a solution of (2R*,6S*)-2-(4-methoxyphenyl)-6-vinylpiperidine (320 mg), vinylacetic acid (0.37 mL), and triethylamine (1.23 mL) in DMF (5 mL), and the reaction solution was stirred at room temperature for nine hours. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 100 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH2:14])=[S:13])[CH:8]=[CH:9][CH:10]=1)(=O)C.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(O)C>[C:19]1([C:17]2[N:14]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[NH2:4])[S:13][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1cccc(NC(N)=S)c1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: Nc1cccc(Nc2nc(-c3ccccc3)cs2)c1
Yield: 82 %

Procedure:
A mixture of N-(3-acetylaminophenyl)thiourea (0.84 g) and 2-bromoacetophenone (0.84 g) in ethanol (10 ml) was refluxed for 15 minutes. After evaporation of the solvent, 3N hydrochloric acid was added thereto and the mixture was refluxed for 30 minutes. The mixture was made basic with sodium bicarbonate and extracted with ethyl acetate. The organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 3-(4-phenylthiazol-2-yl)aminoaniline (0.88 g).
Reaction SMILES: [O:1]([C:8]([O:10][CH2:11][CH2:12][N:13]([CH2:15][CH2:16][O:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH3:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](#N)C.C[Cl:31]>CCOCC>[Cl-:31].[O:1]([C:8]([O:10][CH2:11][CH2:12][N+:13]([CH2:15][CH2:16][O:17][C:18]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])([CH3:27])[CH3:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCOC(=O)Oc1ccccc1)CCOC(=O)Oc1ccccc1
Reactant: CCl
Reactant: CC#N
Solvent: CCOCC
Product: C[N+](C)(CCOC(=O)Oc1ccccc1)CCOC(=O)Oc1ccccc1
Product: [Cl-]
Reaction time: 18 h

Procedure:
To a 500 ml autoclave liner are added N,N-bis[2-((phenoxycarbonyl)oxy)ethyl]-N-methylamine (20.20 g, 56.2 mmol) and acetonitrile (25 ml). The liner is placed in an autoclave and the solution is treated with methyl chloride gas at 85° C. and at a pressure of 60 psig. After 18 h, the cooled mixture is treated with ether (500 ml) precipitating 6 as a white powder, 19.16 g (83%): mp 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[CH2:4][O:5][CH2:6][C:7]([CH3:11])([OH:10])[CH2:8][OH:9].[H-].[Na+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:27]N(C)C=O>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[CH2:4][O:5][CH2:6][C:7]([CH2:11][CH3:27])([OH:10])[CH2:8][O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: ClCc1ccccc1
Reactant: CC(O)(CO)COCc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCC(O)(COCc1ccccc1)COCc1c(Cl)cccc1Cl
Reaction time: 12 h

Procedure:
1-(2,6-Dichlorobenzyloxymethyl)-1-methylethane-1,2-diol (14g) in dimethyl formamide (80 ml) was treated with sodium hydride (1.3 g) at ambient temperature and stirred for 12 h. Benzyl chloride (8 g) was then added and the reaction mixture stirred for a further 4 h. The solvent was then evaporated and 1-(2,6-dichlorobenzyloxy)-3 -benzyloxy-2-ethylpropan-2-ol isolated as a colourless oil by chromatography on silica gel eluted with 9/1 methylene chloride/ether. The structure was confirmed by n.m.r. techniques.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[S:4][C:5]([C:12](O)=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[C:3]1[S:4][C:5]([C:12]([Cl:19])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: O=C(O)c1sc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc(C(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a 500 mL 1-neck RBF under N2 was added 2,4-bis-trifluoromethyl-thiazole-5-carboxylic acid (31.5 g, 1.0 equiv., 0.119 moles) in 25 mL chloroform and 1 mL dimethylformamide (DMF). To this solution was added thionyl chloride (28.3 g, 2.0 equiv., 0.24 moles). The reaction was then heated at reflux for 6 hours. The reaction was cooled to room temperature and concentrated by rotary evaporation at 30° C. to remove solvent. Chloroform was added, 3×25 mL portions, concentrating by rotary evaporation each time, to give 29.8 g (88.4% yield) product as a brown oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][S:17]([O:20]C)(=[O:19])=[O:18]>C(O)C>[CH3:16][S:17]([O-:20])(=[O:19])=[O:18].[C:1]1([NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N+:11]([CH3:16])=[C:10]([NH2:15])[N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COS(C)(=O)=O
Reactant: Cc1cc(Nc2ccccc2)nc(N)n1
Solvent: CCO
Product: CS(=O)(=O)[O-]
Product: Cc1cc(Nc2ccccc2)nc(N)[n+]1C

Procedure:
Compound No. 46. A suspension of 4-phenylamino-2-amino-6-methylpyrimidine, Compound No. 45, (0.25 g) in ethanol (4 mL) was treated with methyl methanesulfonate (0.090 g) and heated at reflux for 5 days. Additional methyl methanesulfonate (0.090 g) was added and the mixture refluxed another 2 days. Concentration and recrystallization from a mixture of methanol, ethyl acetate, and tert-butyl ethyl ether gave 0.10 g of 4-phenylamino-2-amino-1,6-dimethylpyrimidinium methanesulfonate.
Reaction SMILES: CC(N[CH2:6][C@H:7]([OH:21])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]=12)(C)C.CC(NC[C@@H](O)COC1C=CC=[C:35]2[C:40](=[O:41])CCCC=12)(C)C.C(N)(C)(C)C.OC1C=CC=C2C=1CCCC2=O.C([C@@H]1OC1)Cl>>[O:21]1[CH2:6][C@H:7]1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:15]=1[CH2:16][CH2:17][CH2:18][C:19]2=[O:20].[O:41]1[CH2:40][CH2:35]1
Reactant: CC(C)(C)NC[C@H](O)COc1cccc2c1CCCC2=O
Reactant: CC(C)(C)NC[C@@H](O)COc1cccc2c1CCCC2=O
Agent: ClC[C@H]1CO1
Agent: O=C1CCCc2c(O)cccc21
Solvent: CC(C)(C)N
Product: C1CO1
Product: O=C1CCCc2c(OC[C@@H]3CO3)cccc21

Procedure:
The invention relates to a new, industrially advantageous, process for the preparation of the known beta-adrenergic blocking agent, levobunolol, not requiring resolution of racemic bunolol, based on the enantioselective synthesis of an oxiranic intermediate which is then reacted with tert-butylamine. It consists of reacting 5-hydroxy-3,4-dihydro-1(2H)-naphthalenone with (R)-(-)epichlorhydrine in an aprotic solvent, in the presence of a strong base at a temperature of over 90° C., thus obtaining the intermediate chiral oxirane (S)-5-(2,3-epoxypropoxy)-3,4-dihydro-1-(2H)-naphthalenone with more than 95% optical purity, and then, the intermediate chiral oxirane is reacted with tert-butylamine.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=O>C(O)C>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CC(N)=S)cc1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Yield: 91.7 %

Procedure:
To a solution of the compound (209 mg, 1.0 mmol) obtained in Example 178a in ethanol (4 mL) was added 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (267 mg, 1.0 mmol), and the mixture was heated under reflux for 1.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with diluted aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (346 mg, 92%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:4])[CH:2]=[CH2:3].COC1C=CC(O)=CC=1.[CH2:20]([Cl:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[Cl-:27].[C:1]([O:5][CH2:6][CH2:7][N+:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:10])[CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCN(C)C
Reactant: ClCc1ccccc1
Agent: COc1ccc(O)cc1
Solvent: CC(C)=O
Product: C=CC(=O)OCC[N+](C)(C)Cc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a two-necked flask provided with a reflux condenser and a dropping funnel were introduced 85.9 g (0.6 mol) of acryloyloxyethyl-N,N-dimethylamine, 160 g of acetone and 0.1 g of hydroquinone monomethyl ether, which was employed as a polymerization inhibitor, and then mixed homogeneously. After dropping 75.9 g (0.6 mol) of benzyl chloride thereinto within about 15 minutes, the mixture was allowed to stand overnight under stirring at room temperature. Then the reaction mixture was washed with 500 ml of acetone to obtain crystals of acryloyloxyethyl-N,N-dimethylbenzylammonium chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.Cl.Cl.[CH:15]([N:18]1[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][NH:21]2)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:21]1[CH2:20][CH:19]3[CH2:24][CH:22]1[CH2:23][N:18]3[CH:15]([CH3:17])[CH3:16])=[N:7][N:6]=[CH:5]2
Reactant: CC(C)N1CC2CC1CN2
Reactant: Clc1nncc2cc(Br)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CC2CC1CN2c1nncc2cc(Br)ccc12
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 46.7 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 90 mg, 370 μmol), 2-isopropyl-2,5-diaza-bicyclo[2.2.1]heptane dihydrochloride (95 mg, 444 μmol) and potassium carbonate (153 mg, 1109 μmol) in 10 mL acetonitrile was stirred at 130° C. under in a sealed tube. The mixture turned red in about 5 min. The reaction was monitored by MS. After about 1 h at 130° C., MS and TLC showed all starting material was converted to product (M+1=347, 349). The mixture was cooled down to room temperature, and concentrated on a Rotavaporator. After purification by column (eluting with gradient of 2-10% 2M ammonia in methanol to DCM), 2-(6-bromophthalazin-1-yl)-5-isopropyl-2,5-diaza-bicyclo[2.2.1]heptane (60 mg) was obtained as a yellow solid.
Reaction SMILES: C(OC([C@H:8]1[NH:13][C:12]([CH3:18])([C:14]([NH:16][NH2:17])=[O:15])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20])=O)(C)(C)C.CC[N:23](CC)CC.[C:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=O)#[N:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:23]=[C:8]1[NH:13][C@@:12]([C:14]2[O:15][C:33]([C:32]3[CH:31]=[C:30]([CH:38]=[CH:37][CH:36]=3)[C:28]#[N:29])=[N:17][N:16]=2)([CH3:18])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN1C(=O)CC(C)(C(=O)NN)N[C@@H]1C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=N)N[C@](C)(c2nnc(-c3cccc(C#N)c3)o2)CC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.1 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide (CY1; R6=Me, 0.037 g, 0.12 mmol) in DCM (0.3 mL) at 0° C. was added Et3N (0.035 mL, 0.24 mmol, 2 eq) followed by 3-cyanobenzoyl chloride (0.027 g, 0.16 mmol, 1.3 eq). The mixture was stirred at RT for 6 h. The mixture was diluted with DCM (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was then treated with TsCI (0.035 g, 0.18 mmol, 1.5 eq), Et3N (0.046 mL, 0.31 mmol, 2.6 eq), and DMAP (0.002 g, 0.016 mmol, 0.13 eq) in DCM (0.25 mL) at RT for 16 h. The mixture was diluted with DCM (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was treated with 30% TFA/DCM (1 mL) at RT for 1 h. The mixture was concentrated in vacuo and the residue was purified on reverse phase HPLC (B) to give 0.006 g (12%) of 3-(5-((S)-2-imino-1,4-dimethyl-6-oxo-hexahydropyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)benzonitrile as a white solid (CZ1; R6=Me). 1HNMR (CD3OD, 300 MHz): 8.49 (m, 2H), 8.12 (d, 1H), 7.92 (t, 1H), 3.75 (m, 2H), 3.36 (s, 3H), 1.82 (s, 3H). MS (ESI): MH+=311.2, HPLC (A) Rt=4.175 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH3:14].[Si:24]([N:31]1[CH:34]([CH2:35][CH:36]=[O:37])[CH2:33][C:32]1=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CCCCCC.O1CCCC1>[Si:24]([N:31]1[CH:34]([CH2:35][CH:36]([OH:37])[CH2:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:33][C:32]1=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
To a flame dried, 50 ml, 3-neck flask fitted with a N2 inlet, magnetic stirrer, addition funnel, and serum cap are added anhydrous tetrahydrofuran (THF) (10.5 ml) and diisopropyl amine (0.579 ml, 4.13 mmol). The solution is cooled in an ice-methanol bath under N2 and treated with 2.4N n-butyl lithium in hexane (1.72 ml). After being stirred at -10° for 15 mins, the solution is cooled to -78° and treated dropwise over 9 mins with a solution of benzyl acetate (0.620 g, 4.13 mmol) in anhydrous THF (3.5 ml). After stirring 15 more mins at -78° C. the reaction mixture is treated dropwise over 13 mins with a solution of N-(t-butyldimethylsilyl)-4-(2-oxoethyl)-azetidin-2-one (0.894 g, 3.93 mmol) in anhydrous THF (6 ml). The reaction mixture is stirred at -78° an additional 15 mins and then quenched with 2.5N HCl (6 ml). EtOAc (100 ml) is added and the oragnic phase is separated, washed with H2O (2×20 ml), 5% NaHCO3 (20 ml) and brine, dried with MgSO4, and filtered. The filtrate is evaporated i.v. and the residue stripped with φH to yield N-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one (1.432 g) as an oil: ir (neat) 2.87, 5.73, 5.79, 7.57, 7.96, 8.39, 11.92, and 12.16 cm-1 ; mass spectrum m/e 362, 320, 278, 170 and 128.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:24].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1F)[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:19][C:18]1[C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:33]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=4[F:25])[C:3]3=[O:24])[CH2:8][CH2:9]2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 130 °C
Yield: 1.4 %

Procedure:
To a solution of (S)-3-amino-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 150, Step C, 0.30 g, 0.83 mmol) in DMSO (3 mL) was added 3,4-difluorobenzonitrile (0.35 g, 2.5 mmol) and potassium carbonate (0.34 g, 2.5 mmol) and the reaction was heated to 130° C. for 6 hours. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL), and brine (20 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using a gradient of 1:9 to 1:4 EtOAc:DCM as eluent to give a solid, which was further triturated with DCM to give (S)-4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylamino)-3-fluorobenzonitrile (0.006 g, 0.012 mmol, 2% yield). Mass spectrum (apci) m/z=482.0, 483.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]2[N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=[C:14]2[N:13]=[C:12]([CH3:23])[CH:11]=1>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[N:15]3[N:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[N:18]=[C:14]3[N:13]=[C:12]([CH3:23])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cc(Cl)n2nc(C(F)(F)F)nc2n1
Solvent: CCO
Product: Cc1cc(Nc2ccc(Cl)cc2)n2nc(C(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
4-chloroaniline (0.355 g, 2.78 mmol) was added to a well-stirred absolute ethanol solution of 7-chloro-5-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (0.547 g, 2.32 mmol, 15-20 mL). After stirring for 6-8 hours at room temperature, the desired product crystallized and was then filtered. Subsequent purification using column chromatography gave the final product in 66% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:16])=[C:5]([CH3:15])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[F:17][C:18]([F:26])([F:25])[C:19]([C:20]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]2[C:5]([CH3:15])=[C:4]([CH3:16])[S:3][C:2]2=[N:1][C:21]=1[CH3:22])=[O:24]
Reactant: Cc1sc(N)c(C(=O)c2ccccc2)c1C
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc(C)c(C)c2c(-c2ccccc2)c1C(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
To a stirred solution of 50 mg (0.22 mmol) (2-Amino-4,5-dimethyl-thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 15) in 2 ml acetic acid was added 0.03 ml (0.22 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 8 mg (11%) 2,2,2-trifluoro-1-(2,3,6-trimethyl-4-phenyl-thieno[2,3-b]pyridine-5-yl)-ethanone as an orange solid. ES-MS m/e (%): 350 (M+H+, 100).
Reaction SMILES: C1[CH2:5][CH:4]=[CH:3]C=1.[C:6]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C:7]=1[CH2:8][CH2:9][CH2:10]2.[CH2:16](OCC)[CH3:17]>ClCCl>[C:6]123[CH2:5][CH2:4][CH2:3][C:7]1([C:11](=[O:12])[O:13][C:14]2=[O:15])[CH:8]1[CH2:9][CH:10]3[CH:16]=[CH:17]1
Reactant: C1=CCC=C1
Reactant: CCOCC
Reactant: O=C1OC(=O)C2=C1CCC2
Solvent: ClCCl
Product: O=C1OC(=O)C23CCCC12C1C=CC3C1
Temperature: 25 °C

Procedure:
The structure-directing agent (SDA) 8-azonia-8,8-diethyltetracyclo[4.3.3.12,5.01,6]tridec-3-ene cation is synthesized according to the procedure described below. To a solution of freshly cracked cyclopentadiene (40 grams) in 1200 ml of dichloromethane is added 1-cyclopentene-1,2-dicarboxylic acid anhydride (30 grams). The reaction is stirred at room temperature for several days. The desired product, 8-oxa-tetracyclo[4.3.3.12,5.01,6]tridec-3-ene-7,9-dione, is isolated by recrystallization (after stripping off solvent) from 2/1 ethyl ether, dichloromethane with refrigeration.