Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([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)[N:3]=1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[OH:45].N12CCCN=C1CCCCC2>CS(C)=O>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: Nc1ccccc1O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Nc4ccccc4O)nc32)[C@H](O)[C@@H]1O
Temperature: 140 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of 1-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-1-deoxy-N-ethyl-β-D-ribofuranuronamide (0.20 g, 0.038 mmol), 2-aminophenol (0.20 g 1.83 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 ml, DBU) and dimethylsulphoxide (1 ml) was stirred and heated at 140° C. under nitrogen for 6 h, and then left at 21° C. overnight. The mixture was partitioned between ethyl acetate (200 ml) and water (40 ml). The aqueous layer was extracted with more ethyl acetate (50 ml) and the total organic solution was washed (water, 20 ml), dried (Na2SO4) and evaporated. The residue was purified on flash silica eluting with dichloromethane:methanol (19:1), and then by preparative TLC (20×20 cm plate with 2 mm layer of Kieselgel 60 F254 ; Art 5717) in dichloromethane:ethyl acetate:ethanol 9:9:2, and then by preparative HPLC (30 to 70% acetonitrile) to give the title compound (0.018 g) as a cream foam, MH+ =596. Analysis found: C, 52.2, H, 4.3, N, 11.8; C32H33N7O5.2CF3CO2H requires C, 52.5, H, 4.3, N, 11.9%
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:49]=[C:50]([CH3:54])[CH:51]=[CH:52][CH:53]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:61][C:62]([F:81])([F:80])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:70]2[C:71]3[CH2:79][CH2:78][NH:77][CH2:76][C:72]=3[N:73]=[CH:74][N:75]=2)=[CH:65][CH:64]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:50]1([CH3:54])[CH:51]=[CH:52][CH:53]=[C:48]([N:77]2[CH2:78][CH2:79][C:71]3[C:70]([NH:69][C:66]4[CH:65]=[CH:64][C:63]([C:62]([F:81])([F:61])[F:80])=[CH:68][CH:67]=4)=[N:75][CH:74]=[N:73][C:72]=3[CH2:76]2)[CH:49]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cccc(N2CCc3c(ncnc3Nc3ccc(C(F)(F)F)cc3)C2)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 17.3 %

Procedure:
To 2 mL of dioxane was added 10 mol % of palladium(II)acetate (12 mg) and 20 mol % rac-BINAP (58 mg). After stirring for 3 hours, 3-bromotoluene (0.064 ml, 0.53 mmol), cesium carbonate (682 mg, 2.12 mmol), N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (150 mg, 0.51 mmol) and activated molecular sieves (340 mg) were added. The mixture was sonicated for 10 minutes and heated in a sealed tube via microwave at 160° C. for 3 hours in a Personal Chemistry Microwave (Smith Creator). After completion, the mixture was filtered through celite, evaporated and purified by flash chromatography over silica gel using a 0-100% gradient of ethyl acetate/hexanes to give the desired product as a white solid (34 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:2]=2[CH3:1])[CH3:9])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: Cc1cccc(C)c1OC(C)C(=O)O
Product: Cc1cccc(C)c1OC(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 94.7 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.81 g of (2RS)-2-(2,6-dimethylphenoxy)propionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.25 g of the title compound as a colorless foam.
Reaction SMILES: [N:1]1([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[C:65]=1[C:71](=[N:73]O)[NH2:72]>O.CN(C)C=O>[Cl:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[C:65]=1[C:71]1[N:73]=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([N:1]3[C:2]4[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:8][CH2:9][CH2:10]3)=[O:12])[CH2:14][CH2:15]2)[O:20][N:72]=1
Reactant: O=C(O)C1CCN(C(=O)N2CCCc3ccccc32)CC1
Reactant: NC(=NO)c1c(Cl)cccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(N1CCC(c2nc(-c3c(Cl)cccc3Cl)no2)CC1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
0.3 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperidine-4-carboxylic acid, 11 ml of dimethylformamide, 0.67 g of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 0.028 g of 1-hydroxybenzotriazole, 0.91 ml of diisopropylethylamine and then 0.32 g of 2,6-dichloro-N′-hydroxybenzenecarboximidamide are introduced into a 100 ml round-bottomed flask. The reaction medium is stirred at ambient temperature for 1 h 30 and then heated at 95° C. for 20 hours. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed three times with water and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/ethyl acetate gradient from 0/1 to 1/1. 0.18 g of 1-({4-[3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline is obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[N:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=4)[CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+].O>>[Br:24][C:21]1[CH:20]=[N:19][C:18]([C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[CH2:11][N:8]2[C:6]3=[N:7][C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[CH:3][N:4]=[C:5]3[N:10]=[N:9]2)=[N:23][CH:22]=1
Reactant: Brc1cnc(-c2cccc(Cn3nnc4ncc(Br)nc43)c2)nc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cn1cc(-c2cnc3nnn(Cc4cccc(-c5ncc(Br)cn5)c4)c3n2)cn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
2.00 g (3.67 mmol) of 6-bromo-1-[3-(5-bromopyrimidin-2-yl)benzyl]-1H-1,2,3-triazolo[4,5-b]pyrazine, 840 mg (4.04 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 778 mg (7.34 mmol) of sodium carbonate are suspended in 3.7 ml (204 mmol) of water and 15 ml of N,N-dimethylformamide, degassed, evacuated and flushed with nitrogen a number of times. 257 mg (0.367 mmol) of bis(triphenylphosphine)palladium-(II) chloride are added, and the mixture is again evacuated and flushed with nitrogen. The reaction mixture is stirred at 80° C. for 24 h. The reaction mixture is filtered and washed with ethyl acetate and evaporated. The residue is stirred with isopropanol and reacted further without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[CH:26]1([NH:25][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: NC1CCc2ccccc21
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NC4CCc5ccccc54)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 1-aminoindane were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 449 (M+H)+.
Reaction SMILES: Cl.[N:2]1([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30]([N:5]1[CH2:6][CH2:7][CH2:8][N:2]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:3][CH2:4]1)(=[O:31])=[O:32]
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
A mixture of 4-(hexahydro-1H-1,4-diazepin-1-yl)-benzoic acid, ethyl ester hydrochloride (1:2) (0.01 mol) and 2-naphthalenesulfonyl chloride (0.011 mol) in DCM p.a. (150 ml) was stirred at room temperature. NaHCO3 (saturated aqueous solution, 50 ml) was added and the reaction mixture was stirred for 4 hours at room temperature. The layers were separated. The organic layer was dried, filtered and the solvent evaporated. The residue was triturated under 2-propanol, filtered off and dried, yielding 4.5 g (quantitative yield) of 4-[hexahydro-4-(2-naphthalenylsulfonyl)-1H-1,4-diazepin-1-yl]-benzoic acid, ethyl ester (interm. 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][SH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:18](OCC)[CH2:19][Br:20])C.FC(F)(F)C(O)=O>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[CH:18]([CH2:19][Br:20])[S:14][CH2:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: CCOC(CBr)OCC
Reactant: COc1ccc(CCCS)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: COc1cc2c(cc1OC)C(CBr)SCCC2
Reaction time: 8 h

Procedure:
A mixture of 0.67 g of 3-(3,4-dimethoxyphenyl)-1-propanethiol, 1.0 g of bromoacetaldehyde diethylacetal, 0.16 ml of trifluoroacetic acid, and 25 ml. of nitromethane as solvent is stirred at room temperature for 1 hour, stored overnight in the freezer, and then heated at 70° for 2 hours after an additional 0.05 ml trifluoroacetic acid is added. After cooling, the reaction mixture is extracted with methylene chloride and aqueous sodium bicarbonate. The organic layer is taken to dryness, and the residue is chromatographed one time on silica gel with methylene chloride as eluent and a second time with 10% ethyl acetate/Skellysolve B as eluent to yield 7,8-di-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]([CH3:22])[S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([O:20]C)=[O:19])(=[O:8])=[O:7].Cl>CO.O>[CH3:4][N:5]([CH3:22])[S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:18]([OH:20])=[O:19])(=[O:8])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 50 °C

Procedure:
60.2 g of lithium hydroxide monohydrate are added to a solution of 206.7 g of N,N-dimethyl-2-methoxycarbonyl-5-nitrobenzenesulfonamide in 1500 ml of methanol. The mixture is subsequently stirred at 50° C. until conversion is complete. Following the concentration of the reaction mixture under reduced pressure, the residue is taken up in water and is treated at 0° C. with concentrated hydrochloric acid (pH=1). Filtration with suction followed by drying gives the desired compound. Yield: 162.9 g; m.p.: 160–163° C.
Reaction SMILES: [CH:1]1([CH:4]([C:7]2[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[C:5]#[N:6])[CH2:3][CH2:2]1>C1COCC1>[CH:1]1([CH:4]([C:7]2[CH:8]=[N:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[CH2:5][NH2:6])[CH2:3][CH2:2]1
Reactant: N#CC(c1ccc(C(F)(F)F)nc1)C1CC1
Solvent: C1CCOC1
Product: NCC(c1ccc(C(F)(F)F)nc1)C1CC1
Temperature: 100 °C
Yield: 73 %

Procedure:
A solution of Cyclopropyl-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile (93 mg, 0.41 mmol) in THF (2.8 mL) in a 5 mL microwave vial was treated with borane-methyl sulfide complex (0.51 mL, 5.4 mmol). The reaction vessel was capped and the mixture was heated in the microwave reactor for 20 mins at 100° C. The reaction mixture was concentrated in vacuo to yield the crude title compound which was used without further purification (95 mg, purity: 73%, yield: 73%). LCMS (MH+): m/z=231.1, tR (minutes, Method D)=0.40
Reaction SMILES: Br[C:2]1[C:3]([NH2:26])=[N:4][CH:5]=[C:6]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH:9]=2)[CH:7]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:10]2[CH:9]=[C:8]([C:6]3[CH:7]=[C:2]([C:31]4[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=4)[C:3]([NH2:26])=[N:4][CH:5]=3)[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:23]=1
Reactant: Nc1ncc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)cc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(-c3cc(-c4cc(Cl)ccc4F)nc4ncccc34)cnc2N)cn1
Temperature: 130 °C

Procedure:
A slurry of 297 mg (0.65 mmol) 3-bromo-5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-2-ylamine, 270 mg (1.30 mmol) 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 270 mg (1.95 mmol) potassium carbonate in 3 ml DMF was flushed with nitrogen and then 75 mg (0.07 mmol) tetrakis(triphenylphosphine)-palladium were added. This mixture was heated for 30 minutes at a temperature of 130° C. in the microwave. Water was added to the reaction mixture and the resulting precipitate was filtered off and washed with water. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-3-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-ylamine as yellow crystals; HPLC-MS: 1.57 min, [M+H] 431.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]2=1)=[O:4].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][N:14]1[C:13]2[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]=2[C:7]2[C:15]1=[CH:16][CH:17]=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:24])[F:25])[CH:6]=2
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C(=O)C(F)(F)F)cc3c2C1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C(=O)C(F)(F)F)ccc3n2Cc2cccc(F)c2)C1
Yield: 15.9 %

Procedure:
Mix N-[6-(2,2,2-trifluoro-acetyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Preparation 74) (428 mg, 0.93 mmol), m-fluorobenzyl bromide (216 mg, 1.11 mmol), Cs2CO3 (650 mg, 2 mmol) and DMF (10 mL). Warm the reaction at 50° C. for 18 h, cool and partition between water/brine/EtOAc. Separate and dry the organic layer (MgSO4), filter and concentrate to give 590 mg of crude product. Purify by silica gel chromatography, using 10% to 60% EtOAc/hexane to obtain 68 mg (16%) of the title compound as a pale yellow solid. MS (ES) m/z 461 (M+1); HPLC: Rt=3.43 min (95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[CH3:11])=[CH:6][C:5]=1[NH2:14].[I:16]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([C:10]([F:12])([F:13])[CH3:11])=[CH:6][C:5]=1[NH2:14]
Reactant: II
Reactant: COC(=O)c1ccc(C(C)(F)F)cc1N
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COC(=O)c1cc(I)c(C(C)(F)F)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A mixture of 2-amino-4-(1,1-difluoro-ethyl)-benzoic acid methyl ester (1.3 g, 6.04 mmol), I2 (1.53 g, 6.03 mmol) and Ag2SO4 (1.89 g, 6.03 mmol) in EtOH (40 mL) was stirred for 1 h at r.t. The suspension was then filtered and the filtrate diluted with EtOAc and washed once with a 10% aqueous Na2SO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 2-amino-4-(1,1-difluoro-ethyl)-5-iodo-benzoic acid methyl ester (1.98 g, 5.8 mmol, 96%) as a brown solid, ESI-MS: m/z 383 [M+CH3CN+H]+. rt 6.71 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:13][CH2:12]2)[C:5]([O:8]C)=[N:6][CH:7]=1.C(OCC)(=O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[CH2:12][CH2:13][CH:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:16]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1[nH]cc(Cl)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Yield: 49.3 %

Procedure:
In ethanol (8 ml) was dissolved 245 mg of 1-[(5-chloro-2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine. To the mixture was added 7 ml of a 4N-hydrogen chloride-ethyl acetate solution, followed by heating under reflux for 7 hours. An aqueous sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. Ether was added to the resulting oil to be crystallized, and 116 mg of the title compound was obtained as a slight yellow powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC[O:9][C:10]([CH3:12])=[O:11]>CC(O)=O>[CH:3]1([CH2:6][CH2:5][CH2:4]/[CH:3]=[CH:2]\[CH2:1][CH2:12][C:10]([OH:9])=[O:11])[CH2:2][CH2:1][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Solvent: CC(=O)O
Product: O=C(O)CC/C=C\CCCC1CCCCC1

Procedure:
Rf =0.6 in 1:1 hexane-EtOAc with 0.5% AcOH.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:18])[CH2:11][NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[Br:19].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:18])[CH2:11][NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[Br:19]
Reactant: Nc1c(F)cc(C(=O)CNC2CCCC2)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(F)cc(C(O)CNC2CCCC2)cc1Br

Procedure:
m.p. of the hydrochloride: 167°-170° C. (decomp.), was prepared from 4'-amino-3'-bromo-2-cyclopentylamino-5'-fluoroacetophenone and sodium borohydride analogous to Example 49.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:28])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH2:22][O:23]C(C)(C)C)[CH:20]=2)[CH:15]=1.N>C(O)(C(F)(F)F)=O.CO>[NH2:28][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([CH2:21][CH2:22][OH:23])[CH:20]=2)=[CH:15][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CC(C)(C)OCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cnn(CCO)c2)cc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
3-(1,3-benzoxazol-2-yl)-5-[1-(2-tert-butoxyethyl)pyrazol-4-yl]pyridin-2-amine (485 mg) was dissolved in TFA (3 ml). The resulting solution was stirred at 25° C. for 1 hour. A solution 7N of ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethanol (315 mg). NMR Spectrum: (DMSOd6) 3.75-3.81 (m, 2H), 4.17 (t, 2H), 4.94 (t, 1H), 7.40-7.49 (m, 2H), 7.64 (bs, 2H), 7.79-7.82 (m, 1H), 7.83-7.86 (m, 1H), 7.92 (s, 1H), 8.21 (s, 1H), 8.41 (d, 1H), 8.52 (d, 1H); Mass spectrum: M+H+ 322.
Reaction SMILES: [OH:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][C:24]=1[F:35])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[C:19]([O:21]C)=[O:20].O1CCOCC1.[OH-].[Na+]>O.C(OCC)C>[OH:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][C:24]=1[F:35])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)C1CN(CCSc2cccs2)CCC1CCC(O)c1c(F)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: COc1ccc2ncc(F)c(C(O)CCC3CCN(CCSc4cccs4)CC3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A solution of 630 mg of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylate, 6-cm3 of dioxane and 3-cm3 of a 1 N aqueous sodium hydroxide solution was heated with stirring at a temperature in the region of 60° C. for 2 hours. 3-cm3 of a 1 N aqueous sodium hydroxide solution were added and the solution was heated for 1 hour at 60° C. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was taken up in 20-cm3 of water and 20-cm3 of diethyl ether. The aqueous phase was separated after settling out and was then acidified by pouring in 6-cm3 of 1 N hydrochloric acid. The white precipitate formed was extracted with 150-cm3 of ethyl acetate. The organic phase was washed twice with 10-cm3 of a saturated aqueous sodium chloride solution and dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 499 mg of (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylic acid were obtained in the form of a white solid.