Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]([CH3:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:31][C:32]1[C:33]([CH3:38])=[CH:34][CH:35]=[CH:36][CH:37]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]([CH3:30])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(C)(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC(C)(c4ccccc4)CC3)cnc12
Yield: 62.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-methyl-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (210 mg, 0.49 mmol) obtained in step 2 and o-toluidine (0.08 mL, 0.74 mmol), the title compound (153 mg, 63%) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:4][C:3]1([CH3:16])[CH3:15].[C:17]([O:21][C:22](NC(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([NH:1][CH:2]1[CH2:6][N:5]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:4][C:3]1([CH3:15])[CH3:16])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C[C@H](c1ccccc1)N1CC(N)C(C)(C)C1
Reactant: CC(C)(C)OC(=O)NC(C#N)c1ccccc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(NC(=O)OC(C)(C)C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To an ice cooled solution of 3.69 g of 4-amino-3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidine in 40 ml of anhydrous tetrahydrofuran there was added 4.92 g of 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile and the mixture was stirred at room temperature for 1 hr. Solvent was removed under reduced pressure, and to the residue there was added ethyl acetate. The mixture was washed with a 1N sodium hydroxide aqueous solution three times and then dried. Solvent was then removed under reduced pressure. The residue was purified through column chromatography using 200 g of silica gel in a column with chloroform as the eluant containing from 1% to 5% methanol to yield 4.32 g of the titled compound.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][OH:32])[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[C:33](Cl)(=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].O>C1(C)C=CC=CC=1>[C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCOC1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Reactant: CCCCCCCC(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC1O[C@H](COC(=O)CCCCCCC)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Temperature: 92.5 °C
Yield: 70.4 %

Procedure:
9.5 g of (e) and 5 g of octanoyl chloride in 150 ml of toluene was heated under reflux at 90-95° C. for 4 h. After cooling, the reaction mixture was poured into 600 ml of water and extracted with toluene. The organic phases were combined, washed with NaHCO3 then with water. Finally, after drying and evaporating off the solvents, the crude product was purified over silica to recover 8.6 g of (f) (Yield: 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[CH:19][CH:18]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([C:16]([F:15])([F:28])[F:29])=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(C(F)(F)F)cc3)nc2n(CC)c1=O
Yield: 49.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.20 g (11.2 mmol) of 5,6-diamino-1,3-diethyluracil and 2.66 g (12.3 mmol) of 4-trifluoromethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.09 g (yield 49%) of Compound 136 as a white powder.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:5]1([N:9]([CH3:11])[CH3:10])[CH2:8][NH:7][CH2:6]1)[CH3:4].[CH3:12]NCC>>[ClH:1].[ClH:1].[CH2:10]([N:9]([CH3:11])[C:5]1([CH2:3][CH3:4])[CH2:8][NH:7][CH2:6]1)[CH3:12]
Reactant: CCC1(N(C)C)CNC1
Reactant: CCNC
Agent: Cl
Product: CCN(C)C1(CC)CNC1

Procedure:
N,3-Diethyl-N-methyl-3-azetidinamine dihydrochloride was prepared according to procedure described for the preparation of 3-ethyl-N,N-dimethyl-3-azetidinamine dihydrochloride (Example 211), utilizing N-methylethanamine in place of dimethylamine in Part A. LCMS: (M+H)+ 144.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:34][C:33]1[CH:35]=[CH:36][C:30]([S:27]([O:14][CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(N[C@@H](CO)c1ccccc1)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
53.9 g of (R)-2-benzyloxycarbonylamino-2-phenylethanol (198.7 mmol) were dissolved in a mixture of 500 ml of methylene chloride and 80.3 ml (993.5 mmol) of pyridine. 45.5 g (238.4 mmol) of tosyl chloride in 240 ml of methylene chloride were added at 0° C. with stirring and the mixture was stirred at room temperature for 7 hours. A further 11.36 g of tosyl chloride (59.61 mmol) were added. The mixture was stirred at 0° C. for 5 hours. The batch was then allowed to stand overnight at room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate. The organic phase was washed three times with 10% strength aqueous citric acid solution and twice with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide. Yield: 60.9 g (72%). The mother liquor was concentrated, taken up in n-heptane/ethyl acetate (6/4) and chromatographed on silica gel to give an additional yield of 3.5 g (4.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O:10][C:11](=O)[CH2:12][C:13]([CH2:15][Cl:16])=O)C>>[CH:6]1[CH:5]=[CH:4][N:3]2[C:2](=[N:1][C:13]([CH2:15][Cl:16])=[CH:12][C:11]2=[O:10])[CH:7]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccccn1
Product: O=c1cc(CCl)nc2ccccn12
Temperature: 120 °C
Yield: 98.9 %

Procedure:
15 g (159.4 mmol) of 2-aminopyridine was combined with approximately 80 g of polyphosphoric acid and heated to 120° C. to allow stirring. To the resulting solution was added slowly 30.5 mL (223.2 mmol) of ethyl-4-chloroacetoacetate and stirred at 120° C. under nitrogen for two hours. The hot reaction mixture was then poured over 1500 mL of ice water and stirred vigorously. The aqueous layer was separated and extracted with methylene chloride (6×, approximately 6 L). The combined organic layers were washed with saturated NaHCO3 and brine and dried over MgSO4 and activated carbon. The solvent was removed in vacuo yielding 30.7 g (157.7 mmol, 99%) of 2-(chloromethyl)-5-hydropyridino[1,2-a]pyrimidin-4-one as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16](=[O:32])[CH2:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].Br[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:39][CH:40]=1>C1COCC1.O>[C:19](=[N:18][CH:17]([CH2:34][C:35]1[CH:40]=[N:39][C:38]([NH:41][C:42]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:48])=[CH:37][CH:36]=1)[C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:32])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)cn1
Reaction time: 0.25 h
Yield: 103.8 %

Procedure:
84.64 ml (84.64 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added dropwise to a solution of 25.00 g (84.64 mmol) of N-(diphenylmethylene)glycine tert-butyl ester in 185 ml of THF under argon at 0° C. After stirring at this temperature for 15 min, 24.31 g (84.64 mmol) of tert-butyl (5-bromomethylpyridin-2-yl)carbamate were added as solid, and stirring was continued for 1 h. The reaction mixture was cautiously diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. 44.08 g of the crude product were obtained and were reacted further without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][CH:8]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl.C(#N)C>[Br:25][C:5]1[C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (11.61 g, 33.5 mmol) in DCM (70 ml) and acetonitrile (35 ml) at 0° C. under was added 1-bromopyrrolidine-2,5-dione (12.53 g, 70.4 mmol). The reaction was allowed to warm to room temperature and stirred for 20 hours. The mixture was concentrated in vacuo and then purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([Br:4])[C:2]#[CH:3].[Na].[CH:6](=[N:13][OH:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[Br:4][CH2:1][C:2]1[O:14][N:13]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: C#CCBr
Agent: [Na]
Solvent: ClCCl
Product: BrCc1cc(-c2ccccc2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of propargyl bromide (1.51 ml, 20 mmol) in dichloromethane (15 ml) and aqueous sodium hyopchlorite (22.4 ml, 10%, 30 mmol) at 0° C. was added dropwise with stirring benzaldoxime (2.42 g, 20 mmol) in dichloromethane (15 ml). When addition was complete the ice bath was removed and the reaction stirred for a further 2 h. The organic layer was separated and the aqueous layer washed with dichloromethane (2×20 ml) then the combined organic layers dried (MgSO4). Solvent removal under reduced pressure gave a solid which was recrystallised from 40°-60° C. petroleum ether fraction to give the desired isoxazole (2.64 g, 11.1 mmol, 55%); mp 82°-3° C., δH (CDCl3) 4.40(2H, s, CH2 -Br), 6.50(1H, s, CH-4), 7.3-7.9(5H, m, C6H5).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].C(OCC)(=O)C.[CH2:15]([O:22][C:23]([N:25]1[CH2:29][C:28](O)=[CH:27][C:26]1=[O:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[ClH:32]>C(O)C>[ClH:32].[CH2:15]([O:22][C:23]([N:25]1[CH2:29][C:28]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH2:8])=[CH:27][C:26]1=[O:31])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C=C(O)CN1C(=O)OCc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N[C@@H]1CCCC[C@H]1NC1=CC(=O)N(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
(1R,2R)-1,2-diaminocyclohexane 2294 g (20.09 mol) was dissolved in 3.1 L of ethanol to make a solution. To a 100 L glass lined reactor equipped with a stirrer, were added 26.8 L of ethyl acetate, 4635 g of 4-hydroxy-2-oxo-3-pyrroline-1-carboxylic acid benzyl ester (content: 96.2%, 19.12 mol) synthesized according to the methods of Non-Patent Reference 9 and 12.5 L of ethanol, furthermore, a previously prepared ethanol solution of (1R,2R)-1,2-diaminocyclohexane was added at 15 to 21° C. For washing, 2.2 L of ethanol was used. Next, 3.35 L of 6M hydrochloric acid (20.1 mol) was added at 19 to 25° C. For washing, 0.3 L of water was used. The reaction mixture was heated to 60° C., and reacted at the same temperature for 3 hours. While holding the temperature at approximately 60° C., 4.4 L of ethyl acetate was added, the mixture was cooled to 50° C., 2.4 g of seed crystal was added, and the solution was kept at 50° C. for one hour. While holding the temperature at approximately 50° C., 22.3 L of ethyl acetate was added over one hour, the solution was kept at 50° C. for one hour, cooling to 10° C. over 4.6 hours, and kept at 10° C. for another 10 hours. The deposited solid was separated with a centrifuge, and washed with 17.8 L of a cooled mixed solution of ethyl acetate-ethanol (volume ratio: 75:25). The obtained wet solid was dried under reduced pressure at 50° C. for 19 hours to obtain 6342 g of 4-[(1R,2R)-2-aminocyclohexylamino]-2-oxo-3-pyrroline-1-carboxylic acid benzyl ester hydrochloride.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:3].[CH3:30][NH2:31].C1COCC1.[BH4-].[Na+]>CO>[CH3:3][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:31][CH3:30])=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:1]
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Reaction time: 1 h

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 36) (100 mg, 0.254 mmol) was dissolved in methanol (3 mL) and 2M methylamine in THF (0.254 mL, 0.507 mmol) was added. The yellow solution was stirred under nitrogen at room temperature for 135 minutes at which point sodium borohydride (15.35 mg, 0.406 mmol) was added. The reaction was stirred for 1 h then left sitting overnight. The reaction was quenched with sat. aqueous sodium bicarbonate solution (1 mL) and EtOAc (8 mL) was added. A white solid was filtered off (bond elut reservoir) and found to be the desired product (34 mg). The filtrate was partitioned and the organic layer dried. Concentration of the organic layer gave 67 mg of a colourless residue which was applied to a silica 12+S Biotage column and purified eluting with a gradient of 1-5% methanolic ammonia in DCM. Concentration of the product containing fractions gave another batch of the desired product (52 mg).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:31]1[C@H:35]([CH2:36]Br)[CH2:34][CH2:33][C:32]1=[O:38].CCN(C(C)C)C(C)C>C(#N)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:36][C@H:35]3[NH:31][C:32](=[O:38])[CH2:33][CH2:34]3)[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CC[C@@H](CBr)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O[C@H]1CC[C@@H](NC[C@@H]2CCC(=O)N2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To a solution of non-racemic 1-(S)-(1-(R)-(3,5-bis(trifluoro-methyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(amino)cyclopentane from Example 39 in 0.5 mL of acetonitrile was added 50 mg of (2-pyrrolidon-5-(S)-yl)methylbromide and 0.10 mL of DIPEA. The reaction was heated in a sealed vial at 90° C. for 60 h and then evaporated. The residue was purified on a 2×1 mm preparative silica gel plates eluted with 2% TEA in methanol to afford 50 mg of title compound as a white solid. Mass spec (NH3 /CI): 533 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:14]#[N:15]>CN(C=O)C.CCOCC>[F:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:9][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1cc(F)cc(OC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (1.92 g, 48.0 mmol) is slowly added to a stirred solution of cyclohexanol (4.01 g, 40.0 mmol) in DMF (30 ml) at 0-5° C. under nitrogen. After 2.5 hours, 3,5-difluorobenzonitrile (5.56 g, 40.0 mmol) is slowly added over 5 min. The mixture is allowed to warm to room temperature and stirred for an additional 12 hours. The mixture is diluted with ether (150 ml), washed with water, brine (30 ml), dried over Na2SO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate:hexanes (1:10) to provide 3-fluoro-5-cyclohexyloxybenzonitrile as a yellow oil. MS: 220 (M+1).
Reaction SMILES: N1CCCCC1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].Cl>N1C=CC=CC=1>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccs1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccs1
Yield: 90.1 %

Procedure:
Piperidine (2.45 g, 0.056 mol) was added drop wise over a period of 10 min to a stirred solution of thiophene-2-carbaldehyde (4.00 g, 0.036 mol) and malonic acid (1.00 g, 0.18 mol) in pyridine (40 mL) at 0° C. and the resulting reaction mixture was refluxed for 2 h. The reaction mixture was poured into 2N HCl (100 mL) and the precipitated solid filtered. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-(2-thienyl)prop-2-enoic acid (5.00 g, 92%) as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12](N)=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.N([O-])=O.[Na+].[CH3:21][OH:22]>O>[CH3:21][O:22][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:3]2([NH2:2])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:10][CH:11]=1
Reactant: CO
Reactant: Nc1ccc(CC2(N)CCCC2)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC2(N)CCCC2)cc1
Reaction time: 2 h

Procedure:
1.4 g (6.17 mmol) 4-(1-aminocyclopentylmethyl)-phenylamine hydrochloride are placed in 25 mL methanol and at 0° C. combined with 2.24 mL (27 mmol) conc. hydrochloric acid. At this temperature 0.51 g (7.41 mmol) sodium nitrite in 1 mL water are added dropwise within 30 minutes. After 2 hours stirring the reaction mixture is allowed to come up to ambient temperature and then refluxed for 3 hours. The solvents are distilled off and the residue is combined with ethyl acetate. It is washed with aqueous ammonia solution, dried with sodium sulphate and evaporated down. The residue is dissolved in ethanol and combined with 10% hydrochloric acid in ethanol. The product precipitated as a salt is filtered off, washed with ethanol and dried. Yield: 0.56 g (27% over 2 steps, hydrochloride), mass spectroscopy: [M+H]+=206.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[C:1]([NH:9][CH:10]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CNC(=O)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)C(C)C
Yield: 67.8 %

Procedure:
6.8 g of N-benzoylisobutyrylmethylamine, 1.56 g of 61% sodium hydride and 6.1 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(5). 6.54 g of ethyl 3-benzoylamino-3-isobutyrylpropionate are thereby obtained. Yield: 67.7%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: Ic1ccc(-n2cccn2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-n3cccn3)cc2)cc1
Yield: 64.3 %

Procedure:
Followed the same procedure as that of step 1 in Example 133 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (147 mg, 0.5 mmol) and 1-(4-iodo-phenyl)-1H-pyrazole (203 mg, 0.75 mmol) to afford the title product (140 mg, 60% yield).