Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:21]=[S:17]1(=[O:20])[CH2:16][CH2:15][CH:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:19][CH2:18]1
Reactant: [H][H]
Reactant: O=S1(=O)CCC(N2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: O=S1(=O)CCC(N2CCNCC2)CC1

Procedure:
A suspension of 0.57 g (1.85 mmol) 1-benzyl-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazine and 300 mg 10% Pd/C in 30 mL MeOH was hydrogenated at 50° C. and 50 psi hydrogen pressure for 10 h. The catalyst was removed by suction filtering and the filtrate was concentrated by evaporation i. vac. The product was reacted further without purification.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[F:16][C:17]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:26][C:25]3[C:17]([F:16])=[C:18]([C:22]([F:27])=[CH:23][CH:24]=3)[C:19]([NH2:21])=[O:20])[N:4]=2)=[CH:10][CH:11]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(Cl)cc2)nc1COc1ccc(F)c(C(N)=O)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.3 %

Procedure:
To a solution of 4-Bromomethyl-2-(4-chloro-phenyl)-5-methyl-oxazole (0.12 g, 0.42 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.072 g, 0.42 mmol) and potassium carbonate (0.203 g, 1.20 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.01 g, 6%). 1H NMR (DMSO-d6, 400 MHz): δ 2.49 (s, 3H), 5.09 (s, 2H), 7.11 (m, 1H), 7.38 (m, 1H), 7.60 (d, J=8.40 Hz, 2H), 7.85 (br s, 1H), 7.95 (d, J=8.40 Hz, 2H) and 8.13 (br s, 1H). MS ES+ (379.25), HPLC (method I) Rt=16.71 min
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].P(Br)(Br)[Br:28]>COCCOC>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][Br:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (2.30 mmol) in DME was added phosphorus tribromide (0.26 mL, 2.76 mmol), and the reaction was stirred for 3 hours at room temperature. The mixture was cooled to 0° C., quenched with saturated aqueous NaHCO3, and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CCO>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1F
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 3-fluoro-2-methylaniline (2.65 g, 21.2 mmol) in EtOH (25 mL) at 0° C. was added acetic anhydride (2.60 g, 25.5 mmol). The mixture was stirred at rt overnight then concentrated under reduced pressure to give the title compound (3.54 g). LCMS: m/z 168 [M+H]+
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18](Br)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[C:29]1(C)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Pd]>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:19]=2)[CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(Br)cc2o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncc(-c3ccccc3)cc2o1
Yield: 100 %

Procedure:
The 2-(1-BOC-2-(S)-pyrrolidinyl)-6-bromofuro[3,2-b]pyridine (0.2 g, 0.54 mmol) obtained from Example 46a above was dissolved in toluene (2 mL). Phenylbororic acid (0.19 g, 1.62 mmol), palladium (O) tetrakis(triphenyl phosphine) (40 mg) and 2 M Na2CO3 solution (1 mL) were then added to the toluene solution. The resultant mixture was heated under reflux for 16 h. The desired product was extracted with CH2Cl2, dried over MgSO4 and filtered. Solvent was then removed under reduced pressure and the residue was chromatographed (silica gel: Hexane/EtOAc, 5:1 to 2:1) to afford an oil (0.22 g, 100%). MS (CI/NH3) m/z: 365 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 1.32, 1.50 (2s, 9H), 1.90-2.22 (m, 3H), 2.30 (m, 1H), 3.42-3.73 (m, 2H), 4.97-5.20 (m, 1H), 6.92-7.02 (m, 1H), 7.33-7.66 (m, 5H), 7.93 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][C:15]2[C:11](=[CH:12][N:13]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[C:10]=1[CH3:25])=[O:8].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][C:15]2[C:11](=[CH:12][N:13]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=4)[CH2:23][CH2:24]3)[N:14]=2)[C:10]=1[CH3:25])=[O:8]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COCCNC(=O)c1ccc2nn(CC3CCNCC3)cc2c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCCNC(=O)c1ccc2nn(CC3CCN(C(=O)c4ccc(OC(F)(F)F)cc4)CC3)cc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg of the amine prepared in Example 1a were first dissolved in 1.5 ml pyridine. 101 mg of 4-(trifluoromethoxy)benzoyl chloride were then added and the mixture stirred for 30 min at RT. The reaction mixture was then treated with some toluene and concentrated. The residue was taken up in ethyl acetate and washed twice with water, twice with saturated sodium hydrogen carbonate solution (pH 9) and once with saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4. Gradient: ethyl acetate/methanol 0-10%. Yield: 118.2 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C@@H:31]([OH:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:33][C@@H:31]([CH3:32])[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: C[C@H](O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 61.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-2-hydroxy-propyl)-amide (70 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl-amino)-1H-benzoimidazole-5-carboxylic acid (100 mg), (S)-(+)-1-amino-2-propanol (20 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.87-3.78 (m, 1H), 3.64 (bs, 3H), 3.27-3.20 (m, 2H), 1.09 (d, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:4]1.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](F)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:2][N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:23]3[CH:22]=[N:21][CH:20]=[C:19]([F:18])[CH:24]=3)=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:4]1
Reactant: Cn1ccc(NC(=O)c2nccnc2N)n1
Reactant: Fc1cncc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2nccnc2Nc2cncc(F)c2)n1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
3-Amino-pyrazine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (120 mg, 0.47 mmol), 3,5-difluoropyridine (500 mg, 4.4 mmol), cesium carbonate (610 mg, 1.89 mmol) and 1 mL N,N-dimethylformamide were mixed and stirred under microwave irradiation for 60 minutes at 180° C. The reaction mixture was extracted with sat. NaHCO3— solution and three times ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->30:70 gradient). The desired compound was obtained as a yellow solid (24 mg, 16%), MS: m/e=314.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[C:12]([C:18]#[N:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[F:17][C:15]1[CH:16]=[C:11]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])[C:12]([C:18]#[N:19])=[N:13][CH:14]=1
Reactant: Nc1ccc(I)cc1F
Reactant: N#Cc1ncc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ncc(F)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution of 2-fluoro-4-iodoaniline (930.5 mg, 3.93 mmol) and 3,5-difluoropyridine-2-carbonitrile (500 mg, 3.57 mmol) in THF (8 mL) at −78° C., was added LiHMDS (6.1 ml, 7.50 mmol). The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture as diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried with solid Na2SO4 and was concentrated. The resulting residue was purified by flash chromatography in silica (25% ethyl acetate-hexane) to give pure product. LC/MS [7.72 min; 358 (M+1)].
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C[Si](Cl)(C)C.[CH:25]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38]3([O:45][CH:44]=[CH:43][C:42](=[O:46])[CH2:41]3)[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[O:49][CH3:50])([CH3:27])[CH3:26]>C1COCC1.[Cu](I)I>[CH:25]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38]3([O:45][CH:44]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:43][C:42](=[O:46])[CH2:41]3)[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[O:49][CH3:50])([CH3:27])[CH3:26]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)C=CO3)ccc1OC(C)C
Reactant: Br[Mg]c1ccccc1
Agent: I[Cu]I
Agent: C[Si](C)(C)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)CC(c2ccccc2)O3)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
A round bottom flask was heated with a heat-gun under vacuum followed by being flushed with Ar. The process was repeated three times. To the flask, copper iodide (2.32 g, 12.2 mmol) was placed followed by the addition of THF (5 mL). The suspension was purged with argon for 2 minutes and then cooled to −78° C. Phenylmagnesium bromide (122 mL of 1 M, 122 mmol) in THF was added dropwise at −78° C. under argon. The mixture was stirred at −78° C. for 20 minutes. HMPA (44.0 g, 244 mmol) was added. The mixture was stirred at −78° C. for 30 min. TMSCl (26.5 g, 244 mmol) was added to a solution of 3-(4-isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (7.30 g, 20.3 mmol) in THF (25 mL). The above solution was added to the reaction mixture dropwise. The mixture was slowly warmed to room temperature and was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution, repartitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (40-60% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methoxy-benzoyl)-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-8-one (6 g). ESI-MS m/z calc. 437.22, found 438.0 (M+1)+; Retention time: 1.69 minutes (3 minute run).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[C:12]1[CH:17]2[CH2:18][CH:14]3[CH:15]([CH2:16]2)[CH:13]13)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]([NH2:21])[CH3:20]>C1C=CC=CC=1>[CH2:19]([NH:21][CH2:2][CH2:3][O:4][C:5](=[C:12]1[CH:17]2[CH2:18][CH:14]3[CH:15]([CH2:16]2)[CH:13]13)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:20]
Reactant: CCN
Reactant: ClCCOC(=C1C2CC3C(C2)C13)c1ccccc1
Solvent: c1ccccc1
Product: CCNCCOC(=C1C2CC3C(C2)C13)c1ccccc1

Procedure:
A solution of 90 g. (0.345 mol) of β-chloroethyl-{α[tricyclo-(2.2.1.02.6)hept-3-ylidene]-benzyl}-ether and 69 g. (1.53 mol) of ethylamine in 250 ml. of anhydrous benzene was heated for 5 hours to 140° C. in a 1 litre capacity autoclave. After cooling, the ethylamine hydrochloride was filtered off under suction, the mother liquor concentrated in vacuo and the residue subjected to acid-alkaline working up. The basic fraction was fractionated in vacuo.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:10][C:11]1[C:15](B(O)O)=[CH:14][N:13]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:10][C:11]1[C:15]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:14][N:13]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:12]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C#N)cn1
Temperature: 135 °C
Yield: 53 %

Procedure:
To a solution of 6-Chloro-nicotinonitrile (0.2 g, 1.49 mmol) and 3-methyl-1-trityl-1H-pyrazole-4-boronic acid* (0.5 g, 1.36 mmol) in ethylene glycol dimethyl ether (3 ml), was added sodium carbonate (0.36 g, 3.39 mmol) in water (1.5 ml). The reaction mixture was degassed with nitrogen before addition of tetrakis(triphenylphosphine)palladium (0) and then heated in a CEM microwave at 135° C. for 30 minutes (50 W power). Reaction partitioned between water and ethyl acetate, aqueous basified with 2N NaOH, organic extracts were combined, dried (MgSO4) and solvent removed. Crude product suspended in small volume of methanol, white precipitate filtered to afford the title compound (0.32 g, 53% yield). LC/MS: (PS-A2) Rt 4.52 [M+H]+427.26. *This starting material can be made by the method described in EP1382603A1
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][CH:28]=2)=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: COc1nc(P(C)(C)=O)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1nc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 6-(Dimethylphosphoryl)-2-methoxypyridin-3-ylamine (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:21]1([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH2:26][C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-aminobenzoate (0.25 g, 1.654 mmol) in tetrahydrofuran (8.27 ml) was treated with diisopropylethylamine (0.433 ml, 2.481 mmol) and 2-cyclopentylacetyl chloride (0.279 g, 1.902 mmol) and the reaction mixture was stirred at ambient temperature for 2 hours. Concentration and normal phase chromatography provided the title compound.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:15][CH3:16])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([OH:10])=[O:9])C.[CH:17](NC)(C)C>>[CH:15]([N:4]([CH3:2])[C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([OH:10])=[O:9])([CH3:16])[CH3:17]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: CNC(C)C
Agent: Cl
Product: Cc1cc(C(=O)O)cc(N(C)C(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-diethylamino-6-methyl-isonicotinic acid hydrochloride using isopropylmethylamine; LC-MS: tR=0.54 min, [M+H]+=209.09; 1H NMR δ 1.37 (d, J=6.3 Hz, 6H), 2.64 (s, 3H), 3.17 (s, 3H), 4.50-4.60 (m, 1H), 7.16 (s, 1H), 7.62 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:18][CH2:17]1)[CH:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(OCC)(=O)C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:17][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 21.4 %

Procedure:
A mixture of 2.4 g of ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2-fluorobutyrate (a mixture of diastereomers) and 6.4 g of 1,2,4-triazole was subjected to reaction at 90°-100° C. for 8 hours. To the reaction mixture were then added 10 ml of ethyl acetate and 5 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/methanol=20/1) to obtain 650 mg of ethyl 3-(2,4-difluorophenyl)-2-fluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrate (one of the diastereomers).
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)C(OCC)=O)=[CH:11][C:10]=1[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[CH:11][C:10]=1[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cc(C)c(C(=O)c2ccccc2)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc([N+](=O)[O-])cc2)n(C)c1C(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (8.2 g, 20.2 mmol) [prepared by proceeding as described in Example 1, Steps (a) and (b)] was dissolved in a 1:1 mixture of methanol/THF (200 ml). An aqueous solution of LiOH (250 ml, 0.4M, 100.9 mmol) was added and the mixture was stirred at 60° C. for 2 h. The organic solvents were evaporated in vacuo, the aqueous residue was acidified with 10% HCl, and the product was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated under vacuum. Purification on a Florisil® column (hexane-ethyl acetate, 4:1) gave 4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]-nitrobenzene (6.68 g, 99%) as a yellow solid. ##STR22##
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:31][CH2:30][CH2:29]4)=[O:27])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (4.5 g, 12.4 mmol), azetidine (2.53 ml, 37.3 mmole), N-diisopropylethylamine (6.51 ml, 37.3 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 18.3 ml, 31 mmol) in tetrahydrofurane (220 ml) is stirred for 2 hours at 70° C. The turbid solution is concentrated to about 100 ml, cooled, poured on cooled sat. aqueous sodium bicarbonate solution (1000 ml) and the suspension is stirred for 20 minutes. The solid is collected by filtration, washed with little water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (5 g, 100%) as a white solid. mp.: 243-5° C. MS: m/z=402.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]2[NH:21][CH:20]=[C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[C:15]=2[N:16]=[CH:17][N:18]=1.[H-].[Na+].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]2[N:21]([S:38]([CH3:37])(=[O:40])=[O:39])[CH:20]=[C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc23)CC1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cn(S(C)(=O)=O)c3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
tert-Butyl 4-(4-{[2-fluoro-4-(methylsulfonyl)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (3.1 mg, 0.0063 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), sodium hydride (55% in oil, 0.4 mg, 0.0095 mmol) and methanesulfonyl chloride (0.4 mL, 0.0057 mmol) were added under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction liquid was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=10:1) to give the titled compound (0.6 mg, 16.8%) as a pale yellow amorphous.