Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][C:4]1[CH:5]=[C:6]([F:23])[C:7]([C:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[N:8][CH:9]=1.Cl.O1CCOCC1.C(OCC)C>ClCCl>[F:23][C:6]1[C:7]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)=[N:8][CH:9]=[C:4]([CH2:3][CH:2]([OH:1])[CH2:24][OH:25])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc(CC(O)CO)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: OCC(O)Cc1cnc(C2=CCNCC2)c(F)c1
Yield: 91.3 %

Procedure:
A solution of 42 (0.31 g, 0.868 mmol) in dichloromethane (2.0 mL) was treated at 38° C. with 4 mol/L HCl in 1,4-dioxane (4.34 mmol, 1.1 mL) in a sealed vessel for 16 hrs. The resulting suspension was stirred for 1 h with ethyl ether. The solid precipitate was collected on filter paper and washed several times with ethyl ether to afford 200 mg (70%) of 43 as a tan solid which was used directly for the next step. LC/MS (M+1) 253.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCc1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)[nH]n1
Yield: 52.8 %

Procedure:
Hydrazine hydrate (0.300 mL, 6.18 mmol) was added to a stirring room temperature solution of 67 (0.1.7484 g, 6.18 mmol) in EtOH (6.2 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (40 min): Upon cooling, a white crystalline solid precipitated from the reaction. The solid was separated by filtration, washed with EtOH, and dried to obtain pure 68 (0.9092 g, 52.7%): 1H (CDCl3, 300 MHz): δ 12.44 (1H, broad s), 7.21 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.1 Hz), 6.58 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.00 (2H, t, J=7.0 Hz), 2.93 (2H, t, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz) ppm. Partial 13C (CDCl3, 75 MHz): δ 139.12, 131.93, 129.67, 128.50, 106.49, 60.94, 34.72, 14.20 ppm. HPLC: 10.269 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH3:26])=[O:5])[CH3:2].[H-].[Na+].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34]Br.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:20]=[C:21]([CH2:34][C:33]3[CH:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:38]=[C:31]([C:30]([F:29])([F:43])[F:44])[CH:32]=3)[C:22]([Br:25])=[CH:23][N:24]=2)[CH2:8][C@H:7]1[CH3:26])=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Br)cn2)C[C@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Br)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1C
Reaction time: 0.17 h

Procedure:
(2R*,4S*)-4-(5-Bromopyrimidin-2-yl)amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (5.9 g) is dissolved in N,N-dimethylformamide (60 ml), then thereto is added sodium hydride(62.7%, 697 mg) at room temperature, and the mixture is stirred for 10 minutes. After adding 3,5-bis(trifluoromethyl)benzyl bromide (3.85 ml), the mixture is stirred at room temperature for 2 hours. Water and ethyl acetate is added to the reaction solution, the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is crystallized from diisopropyl ether and hexane to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-bromopyrimidin-2-yl)}amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (6.1 g). MS (m/z): 648/650 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]O)=[C:6]([Cl:8])[N:7]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O.[K+].[Br-]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][Cl:21])=[C:6]([Cl:8])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1nc(CO)c(Cl)nc1N
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#Cc1nc(CCl)c(Cl)nc1N

Procedure:
Compound 2 (3.7 g, 0.02 mole) was suspended in 40 ml of chloroform. To this mixture, 1.8 ml of pyridine and 3.0 ml of thionyl chloride were added slowly while stirring. At the end of this addition, the mixture was stirred for four additional hours at room temperature. The solvent was then removed, and the residue was triturated with 100 ml of cold water. After filtration and washing with cold water, the product (4) was dried in air, yielding 4.0 g (91%) of light yellow solid. The melting point of this solid ranged from 173°-174° C. The IR spectrum (KBr) showed absorptions corresponding to --NH2 at 3201 and 3365.8 cm-1, --C≡N at 2237.6, and --C=N-- at 1648.7 cm-1. The nmr spectrum (DMSO-d6) revealed signals at 7.76 δ (2H, s,NH2) and 4.60 (2H,s,CH2C1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:9][N:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCCCCCCl
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(CCCCCCO)c1ccccc1
Yield: 51.8 %

Procedure:
6-Chlorohexyl alcohol (1.4 g), N-methylaniline (1.1 g) and sodium carbonate (1.1 g) were heated at 120° C. for 9 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.1 g of 6-(N-methy-N-phenylamino)hexyl alcohol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]([C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:30](Cl)CCl.CC1C=CN=C(N)C=1C>ClCCl>[C:21]([O:20][C:18]([NH:17][C@H:15]1[CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]([C:25]([O:27][CH3:30])=[O:26])[CH2:14]1)=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Agent: Cc1ccnc(N)c1C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of cis (+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxy-carbonylamino)piperidine-3-carboxylic acid (1.0 eq), methanol (20 eq.) and EDC (1.3 eq) in dichloromethane at a concentration of 0.25 M at 0° C. was added dimethyl-aminopyridine (0.1 eq). After stirring for 48 hours as the reaction was allowed to warm to rt the volatiles were removed in vacuo. Upon addition of ethyl acetate and washing with H2O (3×), 1N HCl, NaHCO3 (sat.) and brine, the solution was dried over MgSO4, filtered, concentrated and purified by column chromatography (25% ethyl acetate/hexanes) to yield cis (+/−)-1-benzyl 3-methyl 5-(tert-butoxycarbonylamino)-piperidine-1,3-dicarboxylate. LCMS (m/z): 293.1 (MH-Boc+); LC Rt=4.09 min
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[F:9][C:10]([F:25])([S:21](F)(=[O:23])=[O:22])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[OH-].[K+]>O>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][S:21]([C:10]([F:9])([F:25])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])(=[O:23])=[O:22]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,3,3-tetrafluoropropan-1-ol (202 grams, 1.52 moles, Sinochem Corp., Beijing, China), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (3M Company, Saint Paul, Minn., 465 grams, 1.52 moles) and water (500 g) were combined in a 3-liter, 3-necked round bottom flask. The flask was equipped with a magnetic stirrer, cold water condenser, thermocouple and an addition funnel. Aqueous potassium hydroxide (45 percent by weight, 211.5 g, 1.7 moles, Aldrich Chemical Co., Milwaukee, Wis.) was added dropwise via the addition funnel at such a rate that the temperature did not exceed 35° C. Once the addition of the potassium hydroxide was complete, the mixture was stirred for 16 hours at room temperature. Precipitated salts were then filtered from the mixture and the lower liquid fluorochemical product phase was separated from the upper aqueous phase. Unreacted 2,2,3,3-tetrafluoropropan-1-ol and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride were removed from the liquid fluorochemical product phase by atmospheric distillation. Approximately 500 g of 2,2,3,3-tetrafluoropropyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate was recovered at a purity of 98.9 percent as determined by gas chromatography analysis.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@H:13]([CH3:22])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].[P:23](Cl)(Cl)(=[O:35])[O: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.C(Cl)[Cl:39]>>[Cl:39][C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[O:24][P:23](=[N:12][C@H:13]([CH3:22])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])=[O:35]
Reactant: C[C@@H](N)C(=O)OCC(C)(C)C
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[C@@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OCC(C)(C)C

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (R)-neopentyl 2-aminopropanoate (3 g), naphthalene-1-yl phosphorodichloridate (2.36 g), TEA (2.52 mL) and DCM (90 mL) were combined to give (2R)-neopentyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate as a crude pale yellow thick oil. The crude compound was taken forward without further purification.
Reaction SMILES: BrCCOC1C=CC(CO)=CC=1.[Cl:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=1.[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](O)=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC>C1COCC1>[Cl:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([Cl:25])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: OCc1ccc(OCCCl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: OCc1ccc(OCCBr)cc1
Solvent: C1CCOC1
Product: ClCCOc1ccc(COc2ccc(Cl)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution of 8.4 grams (0.045 mole) of the mixture of (4-(2-bromoethoxy)phenyl)methan-1-ol and (4-(2-chloroethoxy)phenyl)methan-1-ol, 8.1 grams (0.045 mole) of 4-chloronaphthol, and 13.7 mL (0.054 mole) of tributylphosphine in 500 mL of THF was cooled in an ice bath and 12.6 grams (0.049 mole) of 1-1′-(azodicarbomyl)dipiperidine was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 24 hours. After this time, the solvent was reduced under reduce pressure, yielding a solid. The solid was purified by column chromatography on silica gel, yielding 15 grams of crude product. The crude product was further purified by column chromatography on silca gel, yielding 6.7 grams of title compound.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[C:20]3([CH2:24][CH2:23][N:22]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:21]3=[O:31])[CH2:19][C@@H:18](O)[CH2:17]2)=[CH:13][CH:12]=1.C(Cl)Cl>>[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]2[C:20]3([CH2:24][CH2:23][N:22]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:21]3=[O:31])[CH2:19][C@H:18]([F:7])[CH2:17]2)=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C1N(C2CCCCC2)CCC12C[C@H](F)CN2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethylaminosulfur trifluoride (11 μL, 0.000083 mol) was added to a solution of (3R)-1-(4-chlorobenzyl)-7-cyclohexyl-3-hydroxy-1,7-diazaspiro[4.4]nonan-6-one (10.0 mg, 0.0000276 mol; prepared as in Example 32, derived from peak 2 of step 2) in DCM (1.0 mL, 0.016 mol) at −78° C. The mixture was allowed to gradually warm to RT and stirred for 2 h. The crude reaction mixture was purified by prep. HPLC to afford the desired product. LC/MS: 365.1 (M+1H)+.
Reaction SMILES: [CH:1]1([C:7]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:11][N:10]([C:13](=[O:27])[C@H:14]([N:24]=[C:25]=[S:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:47]1[CH:51]=[C:50]([CH2:52][CH2:53]CN)[N:49]=[CH:48]1.[N:56]12CCCN=C1CCCC[CH2:57]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:1]1([C:7]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:11][N:10]([C:13](=[O:27])[C@H:14]([NH:24][C:25]([NH:56][CH2:57][CH:52]([C:50]3[N:49]=[CH:48][NH:47][CH:51]=3)[CH3:53])=[S:26])[CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCCc1c[nH]cn1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)N=C=S)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=S)NCC(C)c2c[nH]cn2)CC1
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To 65 mg (0.141 mmol) of ethyl 4-cyclohexyl-1-[(R)-2-isothiocyanato-3-(4-methoxy-phenyl)propionyl]piperidine-4-carboxylate in 5 ml of DMF are added 50 mg (0.141 mmol) of 3-(1H-imidazol-4-yl)propylamine bis(trifluoroacetate) (cf. preparation 4-2) and then 0.063 ml (0.425 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction medium is stirred for 2 hours and then hydrolysed by adding aqueous 5% citric acid solution. The organic compounds are extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 80/20 CH2Cl2/MeOH). 22 mg of ethyl 4-cyclohexyl-1-[(R)-2-{3-[2-(1H-imidazol-4-yl)propyl]thioureido}-3-(4-methoxy-phenyl)propionyl]piperidine-4-carboxylate in the form of a pale yellow powder are obtained in a yield of 26%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH:13]([OH:15])[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Yield: 46.2 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.8 g, 2.97 mmol), 3-fluorophenylboronic acid (0.62 g, 4.46 mmol), Pd(PPh3)4 (0.17 g, 0.149 mmol) and Cs2CO3 (0.97 g, 2.9 mmol) to afford the title compound (0.39 g, 46%).
Reaction SMILES: C(CC(O)=O)CC([NH2:7])C(O)=O.O=[C:13]([CH2:17][CH2:18][C:19]([O-:21])=[O:20])[C:14]([O-:16])=[O:15].CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:7][C@@H:13]([C:14]([OH:16])=[O:15])[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C([O-])CCC(=O)C(=O)[O-]
Reactant: NC(CCCC(=O)O)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](CCC(=O)O)C(=O)O

Procedure:
To measure the D-aminoacid transaminase activity, D-α-aminoadipic acid (20 mmolar), α-ketoglutarate (10 mmolar) and pyridoxal phosphate (10 μg/ml) are incubated with the enzyme in potassium phosphate buffer (10 mmolar), pH 8, at a temperature of 37° C. This results in the formation of D-glutamic acid which can be determined by thin-layer chromatography after spraying with ninhydrin.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35]C=[CH:33][CH:32]=1>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([C:23]2[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=2)[C:15]2[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1ccccc1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-phenylnaphthalen-2-yl)acetic acid (136) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using benzeneboronic acid in the Suzuki reaction, giving the title compound (parent form). 1H-NMR: (400 MHz, MeOH-d4): δ 7.67-7.55 (m, 5H); 7.50-7.48 (m, 1H); 7.41-7.39 (m, 1H); 7.33-7.23 (m, 6H); 5.31 (s, 1H); 2.28 (s, 3H); 1.02 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C29H26ClO3: 457.2; Found: 457.2.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[C:14]1([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C>[OH:26][C:20]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:25][CH2:24][N:23]([C:11]([C:8]2[CH:7]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[S:10][CH:9]=2)=[O:13])[CH2:22][CH2:21]1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCC(O)(c2ccccc2)CC1
Yield: 58 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.04 g, 0.2 mmol) and 4-phenyl-piperidin-4-ol (0.041 g, 0.23 mmol) were dissolved in acetonitrile (3 mL). HATU (0.24 mmol) and diisopropylethylamine (0.077 mL, 0.45 mmol) were added and the reaction mixture was stirred. After 1 hour the solvent was evaporated under vacuum and the residue stirred with aqueous sodium hydroxide (1 N, 3 mL) for 0.5 hours. The mixture was diluted with ethyl acetate and washed with brine, dried over magnesium sulphate, filtered and the solvent evaporated under vacuum. The residue was purified by flash chromatography on silica eluting with ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.041 g) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([NH:10][C:11]([C:13]2[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:12])[CH3:9])=[C:4]([Cl:22])[CH:3]=1.[CH:23]1([C:26]#[CH:27])[CH2:25][CH2:24]1.C(N(CC)CC)C.C(OC(=O)C)C>[Cu]I.O>[Cl:22][C:4]1[CH:3]=[C:2]([C:27]#[C:26][CH:23]2[CH2:25][CH2:24]2)[S:6][C:5]=1[CH2:7][CH:8]([NH:10][C:11]([C:13]1[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=1)=[O:12])[CH3:9]
Reactant: C#CC1CC1
Reactant: CC(Cc1sc(Br)cc1Cl)NC(=O)c1cn(C)nc1C(F)F
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cc1sc(C#CC2CC2)cc1Cl)NC(=O)c1cn(C)nc1C(F)F
Temperature: 60 °C
Reaction time: 48 h

Procedure:
In a sulfonation flask a mixture containing of 240 mg (0.58 mmol) 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid[2-(5-bromo-3-chlorothiophen-2-yl)-1-methylethyl]amide, 80 mg (1.15 mmol) cyclopropyacetylene, 10 mg copper(I)iodide, 36 mg (0.05 mmol) bistriphenylphosphine palladium dichloride and 30 ml triethylamine is stirred at 60° C. for 2 days. Then another 80 mg of cyclopropylacetylene is added and stirring continued for 24 hours. After cooling to ambient temperature ethylacetate and water is added and the organic layer separated and washed again twice with water. After drying (sodium sulphate) and distilling off the solvent in a water jet vacuum, the crude product is obtained. Purification is achieved by column chromatography over silicagel (eluent: ethylacetate/heptane 1:1). Yield: 90 mg (23% of theory) of a slightly brown resin (1H-NMR: 0.8/m/2H, 0.9/m/2H, 1.22/d/3H, 1.45/m/1H, 3.01/d/2H, 3.9/s/3H, 4.40/m/1H, 6.28/s (broad)/1H, 6.88/t/1H—CF2H, 6.89/s/1H, 7.85/s/1H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[CH:32]([CH:34]1[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]1)=[O:33]>C1COCC1.O.C(OCC)(=O)C>[OH:33][CH:32]([C:19]1[S:20][C:16]([C:14]2[CH:13]=[C:12]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=3)[CH:11]=[C:10]([CH3:9])[CH:15]=2)=[CH:17][N:18]=1)[CH:34]1[CH2:35][CH2:36][CH:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:38][CH2:39]1
Reactant: COC(=O)C1CCC(C=O)CC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC(C(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: -78 °C

Procedure:
A flask containing THF (5 mL) was cooled to −78° C. LDA (1.8 M in THF/heptane/ethylbenzene, 3.3 mL, 5.95 mmol) was added followed by a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (0.50 g, 1.49 mmol) in THF (5 mL) in one portion and the resulting solution was allowed to stir at −78° C. for thirty minutes. A solution of methyl 4-formylcyclohexanecarboxylate (336 mg, 1.93 mmol) in THF (5 mL) was then added in one portion and the resulting solution was stirred for 1 hour at −78° C. The reaction was then diluted with water and allowed to warm to room temperature. The mixture was then further diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford methyl 4-{hydroxyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylate as a mixture of 4 isomers. MS ESI calc'd. for C24H25F3N4O3S [M+H]+ 507. found 507. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.82 (d, J=5.1, 1H), 7.96 (s, 1H), 7.95 (s, 1H), 7.44 (s, 1H), 7.27 (d, J=4.9, 1H), 7.15 (s, 1H), 6.20 (d, J=5.0, 1H), 3.55 (s, 3H), 2.30 (s, 3H), 1.99 (m, 1H), 1.88 (m, 2H), 1.66 (s, 3H), 1.45 (m, 1H), 1.37-1.15 (m, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]1[CH3:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]1[CH3:14])(=[O:17])[CH3:16]
Reactant: CC1C(N)CCN1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC1CCN(Cc2ccccc2)C1C

Procedure:
3-Amino-1-benzyl-2-methylpyrrolidine [Japanese Laid-Open Patent Publication No. 22699/1980] was allowed to react with acetic anhydride to give 3-acetylamino-1-benzyl-2-methylpyrrolidine, m.p. 51°-54° C. This compound was hydrogenated catalytically in the presence of 5% palladium-carbon to give 3-acetylamino-2-methylpyrrolidine as an oil.