Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C2C(COC([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:47]([OH:49])=[O:48])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.[NH:59]1[C:63]([CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([OH:81])=O)=[N:62][N:61]=[N:60]1.ON1C(=O)C2C=CC=CC=2N=N1.C(Cl)CCl>ClCCl.CO>[NH:62]1[C:63]([CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:47]([OH:49])=[O:48])=[O:81])=[N:59][N:60]=[N:61]1
Reactant: O=C(O)CCCCCCCCCCCCCCCc1nnn[nH]1
Reactant: O=C(O)COCCOCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: O=c1c2ccccc2nnn1O
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)COCCOCCNC(=O)CCCCCCCCCCCCCCCc1nnn[nH]1
Reaction time: 0.17 h
Yield: 38.7 %

Procedure:
To a suspension of 2-chlorotrityl chloride resin (2 g; crosslinked polystyrene) in dichloromethane were added a solution of (2-(2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy)ethoxy)acetic acid (0.55 g, 1.43 mmol) in dichloromethane (15 ml) and then a solution of DIPEA (0.65 ml) in dichloromethane (7 ml). After stirring at room temperature for 20 min methanol (2 ml) was added, and stirring was continued for 10 min. The resin was filtered, washed twice with dichloromethane and once with DMF. The resin was treated with a 20%-solution of piperidine in DMF (2×10 min), and washed extensively with DMF and dichloromethane. A solution of 16-(5-tetrazolyl)hexadecanoic acid (1.0 g, 3.08 mmol), 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one (0.49 g, 3.0 mmol), and EDC (0.58 g, 3.03 mmol) in dichloromethane (25 ml) was added to the resin, and the mixture was shaken for 60 h. The resin was then extensively washed with DMF, dichloromethane and methanol, and suspended in a mixture of trifluoroacetic acid and dichloromethane (25:75; vol). After 0.5 h the resin was filtered, rinsed with dichloromethane, the combined filtrates were concentrated and the residue recrystallized from MeCN to yield 0.26 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31](Br)[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.[OH-].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[C:27]3[C:28]([O:34][CH3:35])=[CH:29][CH:30]=[C:31]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[CH3:39])[CH:32]=3)[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccc(Br)cc1-c1ccc(F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2C)cc1-c1ccc(F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(5′-bromo-4-fluoro-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (50 mg, 0.082 mmol), (2-methylphenyl) boronic acid (22 mg, 0.165 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (20 mg, 0.024 mmol), aqueous potassium hydroxide (55 μL, 3M, 0.165 mmol) and 1,4-dioxane (1 mL) were placed in a sealed tube and subjected to microwave irradiation at 140° C. for 20 minutes to complete the reaction. The crude reaction mixture was purified by preparative TLC on SiO2 (eluted with 20% Ethyl Acetate in hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-fluoro-6′-methoxy-2″-methyl-1,1′:3′,1″-terphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one as a colorless glass. LCMS calc.=617.18; found=618.16 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 7.84 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.36-7.32 (m, 1H), 7.30-7.22 (m, 4H), 7.22-7.18 (m, 1.5H), 7.18-7.14 (m, 0.5H), 7.14-7.11 (m, 1H), 7.11-7.05 (m, 1H), 7.02 (t, J=8.0 Hz, 1H), 5.58 (d, J=8.5 Hz, 0.55H), 5.28 (d, J=8 Hz, 0.45H), 4.90 (d, J=3.5 Hz, 0.45H), 4.09 (d, J=15.5 Hz, 0.45H), 3.88 (d, J=16.5 Hz, 0.55H), 3.844, 3.838 (s, 3H), 3.82-3.75 (m, 1H), 2.32, 2.56 (s, 3H), 0.52 (d, J=6.5 Hz, 1.35H), 0.38 (d, J=6.5 Hz, 1.65H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1)=[O:4].C(OCC)(=O)C>O1CCCC1>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[C:5]([C@@H:3]([OH:4])[CH2:2][Br:1])[CH:13]=[CH:12][C:8]1=2
Reactant: O=C(CBr)c1ccc2sccc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1ccc2sccc2c1
Temperature: -25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A solution of 7.5 g of (+)-diisopinocamphenylchloroborane dissolved in 15 ml of tetrahydrofuran was cooled to -25° C. Thereto was added 4 g of 5-bromoacetyl-benzo[b]thiophene. The resulting mixture was stirred for 4 hours at -20° C. to -15° C. The reaction mixture was added to a mixture of 80 ml of ethyl acetate and 80 ml of ice water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: hexane:ethyl acetate=10:1) to obtain 3.8 g of (R)-1-(benzo[b]thiophen-5-yl)-2-bromoethanol.
Reaction SMILES: [CH2:1](OC1C(F)=CC(Br)=C2C=1C=CN2C)[C:2]1C=CC=C[CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]2[O:34][CH2:33][CH2:32][O:31][C:25]2=[C:26]2[C:30]=1[NH:29][CH:28]=[CH:27]2>>[Br:21][C:22]1[CH:23]=[C:24]2[O:34][CH2:33][CH2:32][O:31][C:25]2=[C:26]2[C:30]=1[N:29]([CH2:1][CH2:2][CH3:3])[CH:28]=[CH:27]2
Reactant: Cn1ccc2c(OCc3ccccc3)c(F)cc(Br)c21
Reactant: Brc1cc2c(c3cc[nH]c13)OCCO2
Product: CCCn1ccc2c3c(cc(Br)c21)OCCO3
Yield: 90 %

Procedure:
Following the procedure (step 2, scheme 33) used to prepare compound 33-3, compound 40-2 gave compound 40-3 in 90% yield as a yellow solid. LCMS: calc 295.0 found 296.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:21])[N:8]2[CH2:11][CH2:12][CH2:13][O:14]C2CCCCO2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:21])[N:8]2[CH2:11][CH2:12][CH2:13][OH:14])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)n(CCCOC3CCCCO3)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: OCCCn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 50 °C

Procedure:
To 4-(2-chloro-8-iodo-9-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-9H-purin-6-yl)morpholine (0.39 g, 0.8 mmol) in methanol (5 mL) was added p-toluenesulfonic acid (10 mg, 0.08 mmol). The reaction was heated at 50° C. for 30 min, whereupon precipitation was observed signaling reaction completion. This was confirmed by analytical LC-MS. The reaction mixture was concentrated in vacuo to give 3-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)propan-1-ol. Copper(I) iodide (9 mg, 0.05 mmol), picolinic acid (10 mg, 0.09 mmol) and potassium phosphate (0.4 g, 1.9 mmol) were combined in oven-dried 50-mL round-bottom flask and evacuated/recycled with N2 atmosphere. Subsequently, 3-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)propan-1-ol was dissolved in anhydrous dimethyl sulfoxide (6.7 mL) and introduced via syringe. The entire mixture was heated at 80° C. for 20 h. LC-MS indicated good conversion to the desired product. The reaction mixture was cooled to room temperature, diluted with water and EtOAc, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC (40 g silica gel column, 0-100% EtOAc in heptane) to give 112 mg of 2-chloro-4-morpholino-8,9-dihydro-7H-[1,3]oxazino[2,3-e]purine (40%). MS (ESI+): m/z 296.2 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[C:37](=[O:49])[N:38]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:39]([CH3:42])[C:40]=3[CH3:41])=[O:35])=[CH:29][CH:28]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:26])[CH2:15][CH2:16]S(C3C=CC=CC=3)(=O)=O)[CH2:9]2)=[CH:6][N:7]=1.C(O[K])(C)(C)C>C1COCC1>[C:14]([N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:5]2[N:4]=[C:3]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:34]([C:36]4[C:37](=[O:49])[N:38]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[N:39]([CH3:42])[C:40]=4[CH3:41])=[O:35])=[CH:31][CH:32]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9]1)(=[O:26])[CH:15]=[CH2:16]
Reactant: Cc1c(C(=O)Nc2ccc(-c3nc(C4CCCN(C(=O)CCS(=O)(=O)c5ccccc5)C4)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: C=CC(=O)N1CCCC(c2cnc(N)c(-c3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)n2)C1
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of the compound prepared in Example 33 (0.0121 g) in anhydrous THF (1.0 mL) at room temperature under N2 was added tBuOK (0.0030 g). The reaction immediately turned yellow, then a darker brown. After 2 hours, the reaction was partitioned between DCM and saturated NaHCO3 solution and separated. The aqueous layer was reextracted with DCM. The organic layers were combined and washed with water, and brine, then dried with Na2SO4 and concentrated. Purification by preparative TLC yielded the title compound (0.0074 g) having the following physical data.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([Cl:42])=[CH:11][C:12]([O:39][CH2:40][CH3:41])=[C:13]([C:15]2[N:16]([C:36](Cl)=[O:37])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.Cl.[CH3:52][S:53]([CH2:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:55])=[O:54]>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:18]2([CH3:20])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[N:16]([C:36]([N:62]3[CH2:61][CH2:60][N:59]([CH2:58][CH2:57][CH2:56][S:53]([CH3:52])(=[O:54])=[O:55])[CH2:64][CH2:63]3)=[O:37])[C:15]([C:13]3[C:12]([O:39][CH2:40][CH3:41])=[CH:11][C:10]([Cl:42])=[C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])[CH:14]=3)=[N:19]2)=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (260 mg, 0.39 mmol, example 45) and triethylamine (350 mg, 3.34 mmol) in methylene chloride (10 mL) was treated with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (110 mg, 0.39 mmol, prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H49N5O6S2Cl3 [(M+H)+] 840.2185, observed 840.2179
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4](=O)[C:3]1=O.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19].O>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[C:3]2[C:4](=[N:19][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[N:20]=2)[C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(C)(C)C(=O)C1=O
Reactant: NC1CCCCC1N
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3

Procedure:
20.0 g of 3,3,6,6-tetramethyl-1,2-cyclohexanedione and 20 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 6 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated acueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 16.0 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]([CH3:10])=[CH2:9].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7][C:8]([CH3:10])=[CH2:9])[CH3:2]
Reactant: CCNCC
Reactant: C=C(C)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C(C)CN(CC)CC

Procedure:
54.86 g (0.75 mol) of diethylamine and 45.28 g (0.50 mol) of 1-chloro-2-methyl-2-propene were dissolved in chloroform (100.14 g), 20.0 g of sodium hydroxide was added, and the system was allowed to react for 15 hours at 70° C. Upon completion of the reaction, the chloroform solution was washed with a sodium carbonate aqueous solution to remove the unreacted diethylamine, diethylamine hydrochloride, and sodium hydroxide, which yielded a chloroform solution of N,N-diethyl-2-methyl-2-propene-1-amine. 150 g of a 4 N hydrochloric acid aqueous solution was added to the chloroform solution, the N,N-diethyl-2-methyl-2-propene-1-amine was converted into a hydrochloride and extracted from the aqueous phase, and the water was removed by freeze drying, which yielded 60.57 g (0.37 mol; 74% yield) of 2-propene-1-aminium, N,N-diethyl-2-methyl, hydrochloride in the form of a white powder. The structure of the 2-propene-1-aminium, N,N-diethyl-2-methyl, hydrochloride thus obtained was confirmed by 1H-NMR (400 MHz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]#[N:19])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]=[C:10]([C:18]([NH:21][OH:22])=[NH:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A stirred mixture of 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carbonitrile (example B.1) (0.5 g, 1.76 mmol), hydroxylamine hydrochloride (0.45 g, 6.48 mol) and sodium carbonate (0.37 g, 3.53 mol) in water (10 mL) and ethanol (10 mL) was heated under reflux conditions for 2 h. The ethanol was removed partly and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration, washed with water and dried to yield the title compound (0.53 g, 94%) as a light brown solid. MS (ISP) 316.9 [(M+H)+]; mp 243° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:14]C)=[N:5][C:6]([CH3:13])=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[CH:2].[ClH:16]>>[Cl:16][C:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]([CH3:13])=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10])=[CH2:2]
Reactant: C#Cc1c(OC)nc(C)nc1C(F)(F)F
Reactant: Cl
Product: C=C(Cl)c1c(C(F)(F)F)nc(C)[nH]c1=O
Temperature: 25 °C

Procedure:
5-ethynyl-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (1.92 g) was added 6N-HCl (20 ml) with stirring and refluxed for 2 hr. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexanethyl acetate). The crude fraction was concentrated, and then washed with hexane to give 5-(1-chlorovinyl)-2-methyl-6-trifluoromethyl-3H-pyrimidin-4-one (1.62 g) as colorless crystalline solid, mp 164-166° C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH2:36][CH3:37])([CH3:35])[CH2:33][CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH2:33][CH3:34])([CH3:35])[CH2:36][CH3:37])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(C)(CC)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)(CC)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 107b (1.8 g, 3.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-methyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (2.5 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([CH:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1c(N)ncc2c(C3CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reaction time: 1 h

Procedure:
A solution of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (5.00 mg, 0.0118 mmol) in EtOAc (2 mL) with palladium (0.53 mg, 0.0050 mmol) on carbon was sealed and flushed with a nitrogen balloon at rt. The nitrogen balloon was replaced with a hydrogen balloon, and the mixture was allowed to stir for 1 h. The hydrogen balloon was removed and replaced with the nitrogen balloon to flush out all hydrogen gas. The palladium was filtered off, and the product was loaded onto a preparatory TLC plate, eluting with 10% (7 N NH3 in MeOH) in DCM to afford the title compound as a yellow solid. 1H NMR (CD3OD, 400 MHz): δ=1.62 (br, s, 2H), 1.83 (d, J=6.8 Hz, 3H), 2.09-2.22 (m, 2H), 2.70-2.85 (m, 3H), 3.11 (br, s, 2H), 6.50-6.57 (m, 1H), 7.10 (t, J=8.5 Hz, 1H), 7.24 (s, 1H), 7.31 (dd, J=9.1, 4.8 Hz, 1H), 7.95 (s, 1H).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]([CH3:29])=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:18]=[C:12]3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]([CH3:29])=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:42])[NH2:28])=[CH:25][CH:26]=4)[N:18]=[C:12]3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 62 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[1.2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 62% of theory, C29H31N5O3 (497.60) Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5) EKA mass spectrum: (M+H)+ =498
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2ncccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1CCCN2
Temperature: 90 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
To a mixture of quinoline-5-carboxylic acid (4 g) in acetic acid (40 ml) was added borane-pyridine complex (8.59 g) at ambient temperature. After stirred for 18 hours, to the reaction mixture was added 1N hydrochloric acid and heated at 90° C. for 1 hour. The mixture was neutralized with aqueous sodium bicarbonate solution and ethyl acetate was added thereto. The precipitate was filtered off. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash silica gel chromatography eluted with chloroform-methanol and crystallized from diisopropyl ether to give 1,2,3,4-tetrahydroquinoline-5-carboxylic acid (1.12 g) as pale brown crystals.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:31]([C:35]([OH:37])=[O:36])([F:34])([F:33])[F:32]>C1(C)C=CC=CC=1>[F:32][C:31]([F:34])([F:33])[C:35]([OH:37])=[O:36].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH:7]([C:6]([OH:30])=[O:5])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)CC(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O

Procedure:
A solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-leucine t-butyl ester (184 mg, 0.57 mmol) in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-leucine trifluoroacetate (183 mg, 0.37 mmol).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH:5]([C:10]1[CH:11]=[C:12]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:31]=[CH:30][C:26]4[N:27]=[N:28][S:29][C:25]=4[CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[S:29]1[C:25]2[CH:24]=[C:23]([CH2:22][N:18]3[CH2:19][CH2:20][CH2:21][CH:16]([C:14]4[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:42])=[O:3])[CH:11]=[C:12]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:34][CH:33]=5)[CH:13]=4)[CH2:17]3)[CH:31]=[CH:30][C:26]=2[N:27]=[N:28]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4nnsc4c3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4nnsc4c3)C2)c1
Temperature: 78 °C

Procedure:
To compound 49a, 2-[5-(1-Benzo[1,2,3]thiadiazol-6-ylmethyl-piperidin-3-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester (67.0 mg, 0.11 mmol) in EtOH (5.0 ml) was added 2M KOH (0.56 ml, 1.1 mmol). The reaction was heated to 78° C. for 3 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (46 mg, 68%). 1H NMR (400 MHz, MeOD) δ ppm 0.89-0.96 (m, 6 H) 1.44-1.55 (m, 1 H) 1.63-1.71 (m, 1 H) 1.92-2.04 (m, 3 H) 2.13 (s, 2 H) 3.12-3/23 (m, 2 H) 3.32-3.39 (m, 1 H) 3.60-3.67 (m, 2 H) 3.76 (t, J=7.83 Hz, 1 H) 4.62-4.71 (m, 2 H) 7.33 (s, 1 H) 7.51 (s, 1 H) 7.57 (s, 1 H) 7.73-7.82 (m, 4 H) 7.90-7.96 (m, 1 H) 8.40 (d, J=8.31 Hz, 1 H) 8.87 (s, 1 H) Calcd for C31H32F3N3O2S (M+H) 567.67, Found 568.3.