Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:32])[N:17]([C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=2[CH3:30])[C:24]([OH:26])=O)[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].F[B-](F)(F)F.[N:38]1([O:47][C:48](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CON>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:32])[N:17]([C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=2[CH3:30])[C:24]([NH:38][O:47][CH3:48])=[O:26])[CH:18]=[CH:19][N:20]=1)([CH3:12])[CH3:13]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(F)cc(C(=O)O)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Agent: CON
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1cc(F)c(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCCl)c2=O)c1
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To 3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoic acid (Example 316c, 0.13 g) in DMF (3 mL) was added O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (0.182 g) and N,N-diisopropylethylamine (0.148 mL). The reaction was stirred for 15 min, then O-methylhydroxylamine hydrochloride (0.047 g) was added. The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle compound (0.13 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[NH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:27])[CH:33]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cccc(N)c1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.447 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3-aminophenylboronic acid (0.310 g) in ethanol (1 ml). The mixture was heated under reflux for 3 hours, then left at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.01 g) were added and the mixture heated under reflux for 3 hours. The cooled reaction mixture was then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane methanol (0→1%). Combination and evaporation of suitable fractions gave the title compound as a pale brown crystalline solid, m.p. 187° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[Na+].[Br-:15]>CC(O)=O.OS(O)(=O)=O.O.[O-]S([O-])(=O)=O.[Cu+2]>[Br:15][C:3]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[I:1]
Reactant: Cc1ccc(N)c(I)c1
Reactant: [Br-]
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Br)c(I)c1
Reaction time: 1.5 h
Yield: 67.5 %

Procedure:
To a mixture of 2-iodo-4-methylaniline (50 g, 214.55 mmol) in HOAc (250 mL), H2SO4 (10 mL), and H2O (40 mL) was added a solution of NaNO2 (14.5 g) in H2O (80 mL) at 0° C. The solution was stirred for 1.5 h. This was defined as mixture A. In another round bottom flask, a mixture of NaBr (107 g), CuSO4 (32.2 g), Cu (38.9 g), H2SO4 (39 mL), and H2O (25 mL) was refluxed for 1.5 h. To this mixture was added mixture A, and the solution was then refluxed for 3 h. The solution was treated with water and extracted with EA (500 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated in vacuo. Purification by column chromatography over silica gel eluted with PE afforded the product as colorless oil (43 g, yield 68%). 1H NMR (300 MHz, CDCl3): δ 7.69 (m, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.00 (m, 1H), 2.26 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.C(N(CC)CC)C.C1(NC2N=CN=C(C(OC)=O)C=2)CCCCC1.C1(NC2N=CN=C(C(OCC)=O)C=2)CCCCC1.[OH-].[Li+]>[Pd].CCO.C1COCC1.CCO.O>[CH:13]1([NH:12][C:4]2[N:3]=[CH:2][N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1cc(NC2CCCCC2)nc(Cl)n1
Agent: [Pd]
Agent: CCOC(=O)c1cc(NC2CCCCC2)ncn1
Agent: COC(=O)c1cc(NC2CCCCC2)ncn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(NC2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 2-chloro-6-(cyclohexylamino)pyrimidine-4-carboxylate (Intermediate 1, 9.20 g; 34.1 mmol), triethylamine (14.3 mL; 102 mmol) and palladium on charcoal (750 mg) in EtOH (1 L) was stirred at RT under an atmosphere of hydrogen for 16 hours. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo to give a mixture of methyl 6-(cyclohexylamino)pyrimidine-4-carboxylate and ethyl 6-(cyclohexylamino)pyrimidine-4-carboxylate. This crude was dissolved in a mixture of THF/EtOH/H2O (3/2/1, 1 L) and treated with an aqueous lithium hydroxide solution (1N, 102 mmol). After 1 hour, the organic solvents were evaporated in vacuo and water was added. The aqueous layer was washed with DCM (200 mL), then acidified to pH 4 by addition of an HCl solution (1N). The aqueous layer was evaporated to reduce the volume by 30-50%. A white solid appeared and was filtered to afford the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:14]([CH:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)=[CH2:15].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2](/[CH:15]=[CH:14]/[CH:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[CH:3][CH:4]=2)[N:12]=1
Reactant: C=CC1CN2CCC1CC2
Reactant: Cc1nc(-c2ccc(I)cc2)no1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(/C=C/C3CN4CCC3CC4)cc2)no1
Temperature: 100 °C
Reaction time: 5 h
Yield: 10.2 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-methyl-1,2,4-oxadiazole (1.43 g), 3-vinylquinuclidine (685 mg), bis(triphenylphosphine)palladium (II) chloride (175 mg), copper (I) iodide (90 mg) and triethylamine (5.0 ml) in dry dimethylformamide (10 ml) was stirred under argon at 100° C. for 5 hours. The dimethylformamide and triethylamine were removed by evaporation. The residue was treated with 2M aqueous sodium hydroxide solution (20 ml) and extracted with dichloromethane (3×20 ml). The organic extracts were washed with water (20 ml), dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using 5% methanol in dichloromethane containing 0.5% ammonia (density, 0.88 g/cm3) as eluent to give E-3-[2-{4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl}ethenyl]quinuclidine (150 mg) as a solid, m.p. 93°-97° C.; NMR: 1.4(1H,m), 1.65(2H,m), 1.8(2H,m), 2.55(1H,m), 2.65(3H,s), 2.8(4H,m), 3.08(1H,m), 3.45(1H,m), 6.5(1H,d), 6.62(1H,d,d), 7.6(2H,d) and 7.82(2H,d).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[C:11]([CH:12]=CC)=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>C(OCC)(=O)C.C(O)(=O)C>[CH3:4][O:5][C:6]1[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:8][CH:9]=[CH:10][C:11]=1[CH:12]=[O:1]
Reactant: O=[O+][O-]
Reactant: CC=Cc1cccc(Oc2ccccc2Cl)c1OC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1c(C=O)cccc1Oc1ccccc1Cl

Procedure:
Ozone gas was introduced into a solution of 2-chlorophenyl 2-methoxy-3-(1-propenyl)phenyl ether (17.60 g) in a mixture of ethyl acetate (120 ml) and acetic acid (5 ml) at 5° C. for an hour. Thereafter, nitrogen gas was introduced to the reaction mixture to remove the excess of ozone gas, and then dimethyl thioether was added thereto. The mixture was washed with aqueous solution of sodium bicarbonate and water successively, dried over magnesium sulfate and then evaporated. The oily residue was dissolved in diethyl ether, washed with an aqueous solution of sodium bicarbonate, dried and then evaporated to give oily 2-methoxy-3-(2-chlorophenoxy)benzaldehyde (7.0 g).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[C:41]([C:47]([F:50])([F:49])[F:48])[CH:40]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:6]([C:5]2[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=2)=[O:8])=[C:41]([C:47]([F:48])([F:49])[F:50])[CH:40]=1
Reactant: COc1ccc(CN)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NCc2ccc(OC)cc2C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Prepared using General Procedure 6: A solution of mono-methyl terephthalate (315 mg, 1.75 mmol), HOBt (395 mg, 2.92 mmol), EDC (562 mg, 2.92 mmol) and DIEA (509 μL, 2.92 mmol) in DMF (10 mL) was stirred at room temperature. After 30 min, 4-methoxy-2-(trifluoromethyl)benzylamine (300 mg, 1.46 mmol) was added as a solution in DMF (2 mL). After stirring for 18 h, the reaction mixture was diluted with NaHCO3 and extracted with EA. The combined organic layers were dried (Na2SO4) and purified by chromatography (EA/hexanes) to provide 418 mg (78%) of methyl 4-((4-methoxy-2-(trifluoromethyl)benzyl)carbamoyl)benzoate INT-52. LCMS-ESI (m/z) calculated for C18H16F3NO4: 367; no m/z observed, tR=3.42 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.13-8.04 (m, 2H), 7.85-7.75 (m, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.05 (dd, J=8.5, 2.7 Hz, 1H), 6.44 (s, 1H), 4.75 (d, J=5.9 Hz, 2H), 3.94 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25]>>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([NH:27][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:26])[CH3:25]
Reactant: COCCOCC(C)(C)N
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: COCCOCC(C)(C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethylamine (CAN 947723-29-7) as starting materials, MS (EI): m/e=363.2 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=[O:42].[Li]N1C(C)(C)CCCC1(C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:41]([C:37]2[S:36][CH:40]=[CH:39][N:38]=2)[OH:42])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: O=Cc1nccs1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3nccs3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 1,3-thiazole-2-carbaldehyde and lithium 2,2,6,6-tetramethylpiperidide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21](N)=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([OH:34])(C)C.C(O)=O>O>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([OH:22])=[O:34])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)nn1
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)nn1
Temperature: 70 °C
Yield: 97.2 %

Procedure:
A mixture of 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxamide (61.7 g), sodium hydroxide (28 g) and isopropanol (400 ml) was heated at reflux for 1 hour. The mixture was cooled to 70° C. and water (800 ml) was added over 30 minutes. The mixture was acidified to pH 3-4 with a solution of formic acid (41.5 ml) in water (200 ml) over 30 minutes, at 25°-30° C. The mixture was cooled to 10° C., the produce filtered off, washed with water and dried to give 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxylic acid (60.2 g, 97.2% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH:9]([F:11])[F:10])[C:4]([F:7])([F:6])[F:5].[F:14]C(F)=C>>[F:1][C:2]([F:12])([F:13])[C:3]([F:14])([CH2:8][CH:9]([F:10])[F:11])[C:4]([F:6])([F:5])[F:7]
Reactant: FC(F)CC(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)F
Product: FC(F)CC(F)(C(F)(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1,4,4-pentafluorobutane may be prepared by reacting commercially available 1,1-difluoroethylene according to the procedure of George L. Fleming et al., supra, to form a product which may then be hydrogenated to form 2-trifluoromethyl-1,1,1,2,4,4-hexafluorobutane which may then be dehydrohalogenated and then hydrogenated to form 2-trifluoromethyl-1,1,1,4,4-pentafluorobutane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Cl[CH:9]([C:15](=O)[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>C(O)C.CCOCC>[CH2:13]([O:12][C:10]([C:9]1[N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[N:7][C:15]=1[CH3:16])=[O:11])[CH3:14]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1cnccn1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1c(C)nc2cnccn12
Yield: 57.9 %

Procedure:
A solution of pyrazin-2-amine (3.6 g, 37.9 mmol) and ethyl 2-chloro-3-oxobutanoate (5.24 ml, 37.9 mmol) in ethanol (30 ml) was heated at reflux for 9 hours. A 1N solution of HCl in ether was added and the mixture was concentrated under reduced pressure. The residue was triturated with 3×50 ml acetonitrile and filtered to yield crude 2-Methyl-imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester (4.5 g, 58%) as an amorphous solid which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]2[NH:20][C@@H:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@:18]3([C:33]4[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[C@H:17]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:15])=[CH:9][CH:8]=1)C.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:34][C:30]1[CH:29]=[C:28]2[NH:27][C:26](=[O:35])[C@:18]3([C@@H:17]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=4[F:43])[C@H:16]([C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([NH:6][CH2:5][C:4]([OH:44])=[O:3])=[CH:8][CH:9]=4)=[O:15])[NH:20][C@H:19]3[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:33]2=[CH:32][CH:31]=1
Reactant: CCOC(=O)CNc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(NCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenylamino)-acetic acid ethyl ester (28 mg, 0.043 mmol) in THF (3 mL) was added LiOH monohydrate (9 mg, 0.199 mmol) in water (1.5 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenylamino)-acetic acid as a white solid (25 mg, 97%). MS (ES+) m/z [(M+H)+]: 613
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[C@@H:19]1([NH:29][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: FC(F)(F)c1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
4′-(Trifluoromethyl)[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: CN(C)C=O.[C:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>O>[C:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([S:26][C:24](=[O:27])[CH3:25])[CH2:14]1)([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
2.7 l of dimetylformamide are placed in a reactor under inert atmosphere. 251.4 g of N-BOC-3(R,S)-methylsulfonyloxy-piperidine are added with warming. At an internal temperature of 50° C. 256.8 g of potassium thioacetate are added at once. After stirring for 90 min at 95° C. the reaction mixture is transferred into a reactor filled with 4 l of water. 4.2 l of petroleum ether are added. After vigorous stirring for 5 minutes the aqueous phase is removed. After readdition of water the pH is adjusted to >8 with sodium hydroxide. The organic phase is separated, washed with water and treated with active charcoal. The solution is evaporated to dryness. After flash chromatography on silica with petroleum ether, toluene, and ethyl acetate and concentration of the product containing solution crystallization occurs on cooling and 110 g of N-BOC-3(R,S)-acetylthio-piperidine are obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C@H:4]([OH:7])[CH2:5][OH:6].[Si:16](OS(C(F)(F)F)(=O)=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:16]([O:7][C@H:4]([CH2:5][O:6][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@H:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[NH2:2])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: N[C@@H](c1ccc(Cl)c(Cl)c1)[C@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
To a solution of 252 (0.50 g, 1.83 mmol) and DCM (5 mL) at RT was added TEA (1.28 mL, 9.17 mmol) followed by TBDMSOTf (1.05 mL, 4.59 mmol) and the reaction was stirred for 30 min. The reaction poured into aq. NaHCO3 and extracted with DCM. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with hexane/EtOAc/DCM (8:1:1) to afford 0.280 g (32.9%) of (1S,2S)-2,3-bis-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)propan-1-amine (254).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12](Cl)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C@H:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:33][CH2:32]2.C(N(CC)CC)C>CC#N.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:24][CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[C:31]5[C:35](=[CH:36][CH:37]=4)[C@H:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:33][CH2:32]5)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Clc1nccc(-c2ccc3c(c2)OCO3)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN)ccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nccc(-c4ccc5c(c4)OCO5)n3)ccc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
4-(1,3-Benzodioxol-5-yl)-2-chloropyrimidine (Example 290,108 mg, 0.46 mmol) and ethyl [(1S)-5-3-aminopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate trifluoroacetate (Example 263, 277 mg, 0.418 mmol) were dissolved in MeCN (2.6 mL) and 1,4-dioxane (2.6 mL), afterwhich triethylamine (0.175 mL) was added. The reaction mixture was stirred at 90° C. for 18 h, and then cooled to rt. The solvents removed under reduced pressure, and the residue was purified by silica gel flash chromatography (1:2 EtOAc/Hexanes) to give the title compound (136 mg, 69%). 1H NMR (400 MHz, CDCl3): δ 1.32 (t, 3H), 1.70-1.79 (m, 1H), 2.15-2.20 (m, 2H), 2.30-2.51 (m, 2H), 2.73 (dd, 1H), 2.80-2.95 (m, 2H), 3.55-3.64 (m, 1H), 3.74 (q, 2H), 4.14 (t, 2H), 4.22 (q, 2H), 5.42 (s, 1H), 6.01 (s, 1H), 6.65 (d, 1H), 6.75 (s, 1H), 6.90 (d, 2H), 7.05 (d, 1H), 7.20 (d, 2H), 8.15 (s, 1H), 8.25 (d, 1H); LC-MS: RT=2.80 min, (M+H)+ 506.3.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([OH:14])=O.Cl.[NH:16]1[CH2:27][S:26][CH2:25][C@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19].C1C2C(=CC=CC=2)CC1CCC(O)=O.Cl.N1CSC[C@H]1C(N1CCCC1)=O>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([CH:25]1[S:26][CH2:27][NH:16][C@@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:14]
Reactant: O=C(O)C[C@H]1CCc2ccccc2C1
Reactant: O=C([C@@H]1CSCN1)N1CCSC1
Agent: Cl
Agent: O=C(O)CCC1Cc2ccccc2C1
Agent: O=C([C@@H]1CSCN1)N1CCCC1
Product: O=C(C[C@H]1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCSC1
Yield: 38 %

Procedure:
Colorless crystals of 3-{3-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-thioprolyl}thiazolidine were prepared in the same manner as in Example 25, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 3-L-thioprolylthiazolidine hydrochloride were used instead of 3-(indan-2-yl)propionic acid and 1-L-thioprolylpyrrolidine hydrochloride, respectively (yield: 38%).