Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23].F[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=1[F:35].C([O-])([O-])=O.[Na+].[Na+].O>CS(C)=O>[F:35][C:26]1[CH:27]=[C:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=[CH:30][C:25]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23]
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)c(F)c1
Yield: 42.9 %

Procedure:
A solution of (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.0 g, 6.3 mmol), 1,2-difluoro-4-(methylsulfonyl)benzene (1.2 g, 6.3 mmol), and Na2CO3 (3.3 g, 32 mmol) in DMSO (20 mL) was stirred at 120° C. for 48 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered then concentrated in vacuo. The material was purified over silica gel (100% EtOAc) to yield (S)-benzyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.3 g, 2.7 mmol, 42%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][CH:6]([CH2:11][CH:12](OCC)OCC)[C:7]([O:9][CH3:10])=[O:8].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO.OS(O)(=O)=O>[Br:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[C:4]2[C:3]=1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5]2
Reactant: CCOC(CC(Cc1cc(F)cc(Br)c1)C(=O)OC)OCC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2c(Br)cc(F)cc2c1
Reaction time: 1 h
Yield: 28 %

Procedure:
A solution of 29 (6.1 g, 16.3 mmol) in MeOH (6 mL) was added dropwise to a suspension of dichlorodicyanobenzoquinone (DDQ, 3.8 g, 16.7 mmol) in 80% aqueous H2SO4 (30 mL) at 0° C. After the addition was completed, the ice bath was removed and stirring was continued for 1 h. The mixture was poured in to ice water (100 mL), then the resulting brown precipitate was filtered, dissolved in ethyl acetate, and washed with H2O (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated rotary evaporation, and purified by column chromatography to give methyl 5-bromo-7-fluoro-2-naphthoate (30) (28%). 1H NMR (600 MHz, Acetone-d6) δ 8.67 (d, J=1.3 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.18-8.14 (m, 1H), 7.95 (td, J=8.7, 8.2, 2.5 Hz, 2H), 3.97 (s, 3H). GC-MS (ES) for C12H8BrFO2 [M+1]+ 283.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:12])[CH2:9][CH2:10][OH:11]>C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]([OH:12])[CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CCCCC(=O)CCO
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: COC(=O)CCCC[C@@H](O)CCO
Reaction time: 20 h
Yield: 84.1 %

Procedure:
A 100 ml autoclave was charged under argon with 3.8 g (20 mmol) of 8-hydroxy-6-oxo-octanoic acid methyl ester, with the Ru-(R)-BINAP catalyst solution prepared under Example 1, and with 20 ml of oxygen-free methanol. The hydrogenation was carried out for 20 hours at 60° C., at a constant pressure of 40 bar pure H2 and with intensive stirring. When the reaction was complete, the solvent was distilled off using a rotary evaporator. Purification of the residue by column chromatography (silica gel, ethyl acetate/n-hexane) yielded 3.2 g (85%) of (R)-6,8-dihydroxyoctanoic acid methyl ester having an enantiomeric excess of 96% (chiral GC).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[F:25][C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:27]=1[S:33]([CH3:36])(=[O:35])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][C:5](=[O:8])[N:6]([C:30]2[CH:29]=[CH:28][C:27]([S:33]([CH3:36])(=[O:34])=[O:35])=[C:26]([F:25])[CH:31]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)[nH]cc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)c(F)c3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
A suspension of tert-butyl 4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (400 mg, 1.22 mmol), sodium hydride (60 wt % in mineral oil, 58 mg, 1.5 mmol) and DMF (8 mL) was purged with argon and then stirred at room temperature for 20 minutes. To the reaction was added 2,4-difluoro-1-(methylsulfonyl)benzene (351 mg, 1.83 mmol) and then heated at 130° C. for 1 hour. The resulting mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 321 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.07-8.14 (m, 1H) 7.35-7.47 (m, 3H) 6.01 (s, 1H) 4.57-4.64 (m, 1H) 3.60-3.69 (m, 2H) 3.44-3.55 (m, 2H) 3.26 (s, 3H) 1.93-2.03 (m, 2H) 1.83-1.93 (m, 2H) 1.49 (s, 9H). MS (ESI) 445 (M−56+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:4][C:5](NC(=O)OC(C)(C)C)=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[BrH:25].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Br:25][C:5]1[CH:4]=[C:3]([O:21][CH:22]([CH3:24])[CH3:23])[C:2]([Cl:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][NH:9][C:10]2=[O:12]
Reactant: Br
Reactant: CC(C)Oc1cc(NC(=O)OC(C)(C)C)c2c(c1Cl)C(=O)NCC2
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Br)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 209.3 %

Procedure:
To a solution of tert-butyl [8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]carbamate (77c, 500 mg, 0.282 mmol) in THF (20 mL) was added HBr (10.0 mL, 88.4 mmol, 48% aqueous solution). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0° C., CuBr (303 mg, 2.11 mmol) was added, followed by addition of NaNO2 (1.07 mL, 1.55 mmol, 100 mg/mL solution). The resulting reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was neutralized with NaHCO3 and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (1×100 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-100% EtOAc/heptanes) to give 5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77d, 188 mg, 42% over two steps) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([OH:12])=[O:11]>>[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=2[CH3:1])=[CH:15][CH:14]=1)([OH:12])=[O:11]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Cc1c(N)cccc1Cl
Product: Cc1c(Cl)cccc1N=Cc1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
2-methyl-3-chloroaniline (0.25 moles) and p-carboxybenzaldehyde (0.25 moles) were ground in a mortar. The mixture was heated, with stirring in a water bath for 1.5 hours. Distillation at reduced pressure gave N-(p-carboxybenzylidene)-2-methyl-3-chloroaniline as a second fraction.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][N:15]=[C:16]=[S:17]>C(OCC)C>[CH3:14][NH:15][C:16](=[S:17])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: CN=C=S
Agent: CCOC(=O)C(=O)c1csc(=N)[nH]1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1csc(NC(=S)NC)n1
Reaction time: 5 h

Procedure:
A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (20 g.) and methyl isothiocyanate (73 g.) was stirred for 5 hours at 90° to 95° C. After the reaction, to the reaction mixture was added diethyl ether. The precipitates were collected by filtration, washed with diethyl ether and then dried to give ethyl 2-[2-[3-(methyl)thioureido]-1,3-thiazol-4-yl]glyoxylate, which can be represented as ethyl 2-[2-[3-(methyl)thioureido]-2,3-dihydro-1,3-thiazol-4-yl]glyoxylate, (21.3 g.), mp. 121° to 123° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[NH:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.S(=O)(=O)(O)O>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[NH:9][C:8]3[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=3[C:6]3[N:12]([CH:3]=[CH:4][N:5]=3)[C:11]=2[CH:13]=1
Reactant: COC(CNC1=Nc2cc(C(F)(F)F)ccc2Nc2ccccc21)OC
Agent: O=S(=O)(O)O
Product: FC(F)(F)c1ccc2c(c1)-n1ccnc1-c1ccccc1N2

Procedure:
In the manner given in Example 5, 8-trifluoromethyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal is treated with concentrated sulfuric acid to give 6-trifluoromethyl-9H-dibenzo[b,f]imidazo-[1,2-d][1,4]diazepine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1>CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Fc1ccccn1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)C1
Temperature: 120 °C
Yield: 98.3 %

Procedure:
A mixture of 2-fluoropyridine (1.0 g, 10.3 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (1.80 g, 9.66 mmol) was heated at 120° C. for 5 h. After cooling to RT, the solid formed was treated with ether, filtered, and washed with ether. The solid was collected and dried to give the desired product (2.50 g, 98.2%). LCMS: (M+H)=264.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH3:15]>CCO>[NH2:15][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: N
Solvent: CCO
Product: NCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 68 %

Procedure:
4-(Bromomethyl)-3-nitrobenzoic acid (3.2 g; 12.3 mmol) was dissolved in 8% NH3 in EtOH (300 mL) and the resulting solution was stirred at room temperature. After 22 h the solution was evaporated and the residue suspended in H2O (70 mL). The suspension was stirred for 15 min and filtered. The collected solid was suspended in H2O (40 mL) and dissolved by the addition of few drops of 25% aq. NH4OH (pH 12), then the pH of the solution was adjusted to 6 by addition of 6 N HCl. The precipitated solid was filtered, and washed sequentially with MeOH (3×5 mL), and Et2O (10 mL) and was vacuum dried (1.3 kPa; P2O5) to give 4-(aminomethyl)-3-nitrobenzoic acid as a pale brown solid (1.65 g; 8.4 mmol). Yield 68%.
Reaction SMILES: O1C2(CCC(NC)CC2)OCC1.[BrH:13].Br.[CH2:15]([NH:18][CH:19]1[CH2:28][CH2:27][C:22]2[N:23]=[C:24]([NH2:26])[S:25][C:21]=2[CH2:20]1)CC>>[BrH:13].[BrH:13].[CH3:15][NH:18][CH:19]1[CH2:28][CH2:27][C:22]2[N:23]=[C:24]([NH2:26])[S:25][C:21]=2[CH2:20]1
Reactant: CCCNC1CCc2nc(N)sc2C1
Agent: Br
Agent: CNC1CCC2(CC1)OCCO2
Product: CNC1CCc2nc(N)sc2C1
Yield: 62 %

Procedure:
N6-Methyl-4,5,6,7-tetrahydro-benzothiazole-2,6-diamine dihydrobromide (3B) is prepared from 3A as described for 1B.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:5]2=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[BH4-].[Na+].CC(C)=O.[Cl-].[NH4+]>CO>[OH:13][CH:12]1[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)CCCCC2O
Reaction time: 1 h
Yield: 96 %

Procedure:
In an atmosphere of argon, ethyl 2-methyl-5-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (400.0 mg, 1.62 mmol) was dissolved in methanol (5.0 ml), and the solution was mixed with sodium borohydride (91.9 mg, 2.43 mmol) at 0° C. and stirred at the same temperature for 1 hour. Acetone was added dropwise to the reaction solution at 0° C. to decompose excess sodium borohydride and then the thus treated reaction solution was mixed with saturated ammonium chloride aqueous solution, extracted with ethyl acetate and washed with water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=2:1) to obtain the title compound (387.7 mg, 96.1%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:25]
Reactant: COC(=O)CC(=O)Cl
Reactant: Cc1cc(Br)cc(C(=O)c2ccccc2)c1N
Product: COC(=O)CC(=O)Nc1c(C)cc(Br)cc1C(=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-5-bromo-3-methyl-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. Light yellow solid. MS (ESI): 392.1 (M+H)+.
Reaction SMILES: O[C:2](C(F)(F)F)=O.[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(#N)C.O>CO>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH2:18][N:19]([CH3:2])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH2:26][CH2:27]1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CNCC4)CC2)c(F)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2C1
Reaction time: 0.08 h
Yield: 28.1 %

Procedure:
A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (155 mg, 0.287 mmol) in MeOH (2.87 mL) was treated with DIPEA (0.100 mL, 0.575 mmol), formaldehyde (0.021 mL, 0.29 mmol), and after stirring for 5 min, sodium triacetoxyborohydride (122 mg, 0.575 mmol). The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was filtered and purified by HPLC (Pump: Waters 2525 or 2545; MS: ZQ; Software: MassLynx. A Xbridge™ C18, 5 μm, ID 30×75 mm column was used and eluted with 40% to 95% of 2080 (v/v) water/ACN (10 mmol NH4HCO3, pH 9.5-10) and water (10 mmol NH4HCO3, pH 9.5-10)) to give the title compound as an off-white semisolid (35.4 mg, 28.0%). 1H NMR (500 MHz, methanol-d4) δ ppm 1.95 (m, 2H), 2.12 (m, 2H), 2.47 (s, 3H), 2.79 (m, 4H), 2.96 (ddd, J=12.4, 8.8, 3.2 Hz, 2H), 3.35 (m, 2H), 3.49 (s, 2H), 3.75 (td, J=14.6, 4.4 Hz, 2H), 4.43 (tt, J=7.7, 3.5 Hz, 1H), 6.03 (m, 1H), 6.86 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.16 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 440.4.
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14]>>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: CC(C)S(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)C(C)C)n1

Procedure:
In an analogous manner to that described in Example 20, 3-isopropylsulphonyl-1,2,4-triazole was reacted with dipropylcarbamoyl chloride (4 hours reflux) to give 1-dipropylcarbamoyl-3-isopropylsulphonyl-1,2,4-triazole, m.p. 61° - 63° C. Elemental analysis satisfactory.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:15]([NH:17][CH2:18][C:19]#[N:20])=[O:16])[C:9](F)(F)F)=[CH:4][CH:3]=1.C[N:26]([CH:28]=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[C:19]([CH2:18][NH:17][C:15](=[O:16])[C@@H:14]([O:13][C@@H:8]([C:9]1[CH:6]=[CH:7][C:2]([C:28]#[N:26])=[CH:3][CH:4]=1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])#[N:20]
Reactant: CN(C)C=O
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(C#N)cc1)C(=O)NCC#N
Temperature: 80 °C

Procedure:
To a solution of 2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamide from example 69 step 5 (2.03 mmol, 1.0 g) in DMF (2.5 mL), was added zinc cyanide (1.22 mmol, 144 mg) followed by palladium tetrakistriphenylphosphine (0.08 mmol, 92 mg). The mixture was degassed three times via the freeze-thaw method. The mixture was heated at 80° C. overnight. The next day, more zinc cyanide (0.61 mmol, 72 mg) and tetrakistriphenylphosphine (0.04 mmol, 46 mg) were added The mixture was heated at 80° C. overnight. The mixture was cooled to r.t. and diluted with AcOEt (20 mL). The phases were separated and the organic extract was washed with ammonium chloride, brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification: 50:50 (AcOEt:Hex.) gave the title amide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:18]=[C:19]([C:23]3[N:28]=[C:27](Cl)[CH:26]=[C:25]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH:36][CH2:37][C:38]1[S:42][C:41](B(O)O)=[CH:40][CH:39]=1.[F-].[Cs+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[OH:36][CH2:37][C:38]1[S:42][C:41]([C:27]2[CH:26]=[C:25]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:24]=[C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([NH:16][C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:15])[CH:18]=3)[N:28]=2)=[CH:40][CH:39]=1
Reactant: OCc1ccc(B(O)O)s1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nc(Cl)cc(N4CCOCC4)n3)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nc(-c3ccc(CO)s3)cc(N3CCOCC3)n2)c1)C1CCNCC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A mixture of 2-[3-(1-tert-butoxycarbonylpiperidin-4-ylcarbonylamino)phenyl]-4-chloro-6-morpholinopyrimidine (0.054 g), 5-hydroxymethylthien-2-ylboronic acid (0.021 g), caesium fluoride (0.046 g), a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with methylene chloride (3 mg), and methanol (2 ml) was stirred and heated to 120° C. using microwave radiation for 20 minutes under an atmosphere of nitrogen in a sealed glass tube. The resultant reaction mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using an increasingly polar gradient of 0% to 5% methanol in methylene chloride as eluent. There was thus obtained 2-[3-(N-tert-butoxycarbonylpiperidin-4-ylcarbonylamino)phenyl]-4-(5-hydroxymethylthien-2-yl)-6-morpholinopyrimidine as a gum. Trifluoroacetic acid (2 ml) was added to the material so obtained and the mixture was stirred at ambient temperature for 30 minutes. The mixture was evaporated and the residue was purified by HPLC using a Waters ‘Xterra’ preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 1% of a concentrated (d=0.88) aqueous ammonium hydroxide solution) and acetonitrile as eluent. There was thus obtained the title compound as a solid (0.015 g); NMR Spectrum: (DMSO-d6) 1.55-1.66 (m, 2H), 3.04 (d, 2H), 3.77 (d, 8H), 4.69 (d, 2H), 5.57 (t, 1H), 7.05 (d, 1H), 7.19 (s, 1H), 7.4 (t, 1H), 7.9-7.95 (m, 2H), 8.07 (d, 1H), 8.48 (s, 1H), 10.01 (s, 1H); Mass Spectrum: M+H+480.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[CH3:12][C:13]1[C:14]([N:18]=[C:19]=[S:20])=[CH:15][S:16][CH:17]=1.C(Cl)Cl.CO>C1COCC1>[NH2:11][C:5]1[C:4]([C:1]([OH:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][C:19]([NH:18][C:14]1[C:13]([CH3:12])=[CH:17][S:16][CH:15]=1)=[S:20]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1cccc(C(=O)O)c1N
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)Nc1cccc(C(=O)O)c1N

Procedure:
is obtained analogously to the procedure described in example 25 a) from 3-carboxy-1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF, followed by medium-pressure chromatography on silica gel using a mixture of 12 parts of methylene chloride and 1 part of methanol. Amorphous product.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1.[CH2:22]([SH:24])[CH3:23].O>CN1C(=O)CCC1>[CH2:22]([S:24][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1)[CH3:23]
Reactant: CCS
Reactant: FC(F)(F)c1ccc2oc(-c3sccc3Br)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCSc1ccsc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.11 g of sodium hydride (60%) was added to a solution of 0.65 g of 2-(3-bromothiophen-2-yl)-5-(trifluoromethyl)benzoxazole and 0.2 ml of ethanethiol in NMP 6 ml at 0° C., and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous salt solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.8 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethyl)benzoxazole (Compound of Present Invention (36)).