Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[O:23][CH2:24][C:25]#[N:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn]([N:43]=[N+:44]=[N-:45])(CCCC)CCCC)CCC>C(OCC)(=O)C.Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[O:23][CH2:24][C:25]3[NH:45][N:44]=[N:43][N:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCOc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2nc(CCc3cccc(OCc4nnn[nH]4)c3)oc2-c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 66.3 %

Procedure:
A mixture of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetonitrile (1.60 g, 4.2 mmol) and tri-n-butyltin azide (1.45 g, 4.4 mmol) was stirred at 140° C. under an atomosphere of nitrogen. After 20 hours, the mixture was cooled, diluted with ethyl acetate (300 mL) and 1N HCl (200 mL) and the mixture stirred for 2 hours. The aqueous phase was removed and the organic phase added to 0.1M potassium fluoride solution. After stirring overnight, the organic layer was separated, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel using a mixture of chloroform and methanol (10:1) as eluent to give 5-[[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]methyl]-1H-tetrazole (1.18 g, 66%) after recrystallization from a mixture of hexanes and CH2Cl2 m.p. 138.5°-140° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:21][CH2:22][CH3:23].Cl>>[F:12][C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:17][C@@H:16]([CH3:20])[N:15]([CH2:21][CH2:22][CH3:23])[C@@H:14]([CH3:13])[CH2:19]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: CCCN1[C@H](C)CNC[C@@H]1C
Agent: Cl
Product: CCCN1[C@H](C)CN(c2ccc(F)c(C(F)(F)F)c2)C[C@@H]1C

Procedure:
Beginning with 5-bromo-2-fluorobenzotrifluoride and cis-2,6-dimethyl-1-propyl-piperazine, the title compound was recovered by the procedure described in Preparation 9: m.p. 221° C. (HCl), MS m/z (rel. intensity, 70 eV)) 318 (M+, 32), 289 (74), 112 (bp), 70 (71), 56 (85).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][C:36]3[CH:41]=[C:40]([O:42][CH3:43])[N:39]=[C:38]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:37]=3)[CH2:12]1)[C:8](=[O:50])[NH:7]2)=[O:5])C.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(Cl)Cl.O>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]2[C:14](=[O:34])[N:13]3[CH:9]([CH2:10][CH:11]([O:35][C:36]4[CH:41]=[C:40]([O:42][CH3:43])[N:39]=[C:38]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[N:37]=4)[CH2:12]3)[C:8](=[O:50])[NH:7][C:6]3([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]3)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(Oc3cc(OC)nc(-c4ccccc4)n3)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(OC)nc(-c5ccccc5)n4)CN3C2=O)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
Compound 6e (410 mg, 0.60 mmol) was dissolved in a 2:1:1 mixture of THF:MeOH:H2O (144 ml). LiOH (1 M, 6 ml) was added and the reaction mixture was stirred at RT over night. 5% Citric acid was added followed by DCM. The organic layer was dried (MgSO4), filtered and evaporated which gave the title compound (305 mg, 78%), MS (M+H)+656.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:4][CH2:3]1.[C:17]1([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C1COCC1>[C:17]1([C:23]2[N:24]=[N:25][N:26]([CH:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)=[O:9])[CH2:4][CH2:3]3)[N:27]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Oc1cccnc1)N1CCC(O)CC1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Oc1cccnc1)N1CCC(n2nnc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a mixture of pyridin-3-yl 4-hydroxypiperidine-1-carboxylate (300 mg), 5-phenyl-1H-tetrazole (217 mg), triphenyl phosphine (460 mg), and THF (3 mL) was added dropwise a 2.2 M solution of diethyl azodicarboxylate in toluene (0.8 mL), followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=99/1 to 90/10), and purified again by silica gel column chromatography (hexane/ethyl acetate=70/30 to 0/100). To the purified product was added hexane/ethyl acetate, followed by stirring, and then the resulting solid was collected by filtration and dried to obtain pyridin-3-yl 4-(5-phenyl-2H-tetrazol-2-yl)piperidine-1-carboxylate (250 mg) as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.O.[OH-].[Na+]>C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:19])[F:20])[C:9]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[C:8]2[CH3:29]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(Cl)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.52 g), methanol (20 mL), water (2.0 mL) and 5.0 M aqueous sodium hydroxide solution (1.0 mL) was stirred at room temperature for 1 hour. The pH of the mixture was adjusted to 5 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration, washed with water and acetonitrile and then dried to afford title compound as an off-white solid, 0.41 g.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:20])[C:12]([Cl:19])=[C:13]([Cl:18])[C:14](=[O:17])[C:15]=1[Cl:16].Cl.C(OCC)(=O)C>C1COCC1>[Cl:9][C:10]1[C:11]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([OH:20])[C:12]([Cl:19])=[C:13]([Cl:18])[C:14](=[O:17])[C:15]=1[Cl:16]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.82 g (3.33 mmol) of 2,3,5,6-tetrachloro-1,4-benzoquinone in 26 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.04 g of the desired product (yield 94%).
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[N:24]=1)([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:31].CO>>[C:19]([O:18][C:16](=[O:17])[NH:15][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[N:24]=1)([CH3:14])[CH2:12][O:11][C@@:5]([C:4](=[O:3])[NH2:31])([CH3:10])[C:6]([F:7])([F:8])[F:9])([CH3:20])([CH3:22])[CH3:21]
Reactant: N
Reactant: CCOC(=O)[C@@](C)(OCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)n1)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C)(CO[C@](C)(C(N)=O)C(F)(F)F)c1cccc(Br)n1

Procedure:
A solution of (R)-2-[(RS)-2-(6-bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propoxy]-3,3,3-tri-fluoro-2-methyl-propionic acid ethyl ester (3.0 g, 6.01 mmol) in 7N NH3/MeOH (6.5 ml) was stirred in a sealed glass vial at 55° C. for 72 h. The reaction mixture was concentrated to leave the title compound as a colourless solid that was used in the next step without further purification. HPLC RtH4=1.12, 1.14 min (diastereomers); ESIMS: 470, 472 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14](C3CCCCO3)[N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:21])[C:3]=1[C:4]#[N:5].Cl.CCO.C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:21])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1c(F)cc(-c2ccn[nH]2)cc1Cl
Yield: 94.1 %

Procedure:
2-Chloro-6-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (1.09 g, 3.55 mmol) was stirred with 10% HCl (g)/EtOH-solution (50 ml) at room temperature for 1 h. Reaction mixture was poured into water (50 ml) and made slightly alkaline with saturated NaHCO3 solution. Thus resulting precipitate was filtered, washed with water and dried in vacuum to obtain 0.74 g (94%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.06 (d, 1H), 7.94 (dd, 1H), 8.05 (m, 1H), 13.4 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[NH:38][C:37]([C@@H:39]5[CH2:43][CH2:42][CH2:41][N:40]5C(OC(C)(C)C)=O)=[N:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:51][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].Cl.[CH3:56][O:57][C@H:58]([CH3:68])[C@H:59]([NH:63][C:64]([O:66][CH3:67])=[O:65])[C:60]([OH:62])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CN(C=O)C>[CH3:56][O:57][C@H:58]([CH3:68])[C@H:59]([NH:63][C:64](=[O:65])[O:66][CH3:67])[C:60]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:24]=[C:25]4[C:20](=[CH:21][CH:22]=3)[C:18]3[NH:19][C:15]([C@@H:14]5[C@@H:13]6[CH2:51][C@@H:10]([CH2:11][CH2:12]6)[N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:52]([CH3:53])[CH3:54])=[N:16][C:17]=3[CH:27]=[CH:26]4)=[CH:29][CH:30]=2)=[CH:35][N:36]=1)=[O:62]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Temperature: 35 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
(S)-tert-butyl 2-(5-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (73 mg, 0.10 mmol) in DCM (3 mL) and MeOH (3 mL) was added HCl (4M in dioxane, 0.5 mL). The solution stirred for 3 h at 35° C., after which the solvent was removed. The intermediate (31 mg, 0.13 mmol) was dissolved in DMF (1 mL). (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (9 mg, 0.05 mmol), HATU (19 mg, 0.05 mmol), and DIPEA (0.04 mL, 0.25 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (23.1 mg). LCMS-ESI+: calc'd for C44H52N8O7: 804.93 (M+); Found: 806.34 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: OCC[C@@H]1CCCN1CCc1ccc2c(c1)CCC2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCC[C@@H]1CCCN1CCc1ccc2c(c1)CCC2
Yield: 91 %

Procedure:
A solution of (2S)-(2-hydroxyethyl)-1-[2-(indan-5-yl)ethyl]pyrrolidine (0.99 g, 3.8 mmol--see Preparation 17) and thionyl chloride (1 ml) in chloroform (15 ml) was heated under reflux for 3 hours and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate solution and the organic layer was dried over magnesium sulphate and evaporated to give the title compound (956 mg, 91%) as a brown oil which was not characterised before use (Example 24).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[O:20][CH3:21])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[O:20][CH3:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:43][CH:40]2[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][CH2:39]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(C(F)(F)F)cc2OC)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(2-methoxy-4-trifluoromethyl-phenyl)-methanone (Example 203) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C19H23N5O4SF3 [(M+H)+] 474.1418, observed 474.1418.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9](=[O:25])[C:10]3[N:11]=[CH:12][N:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[C:14]=3[N:15]=2)=[CH:3][CH:2]=1.[NH2:39][C:40]1[CH:44]=[CH:43][O:42][N:41]=1>O=S(Cl)Cl>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9](=[O:25])[C:10]3[N:11]=[CH:12][N:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:39][C:40]4[CH:44]=[CH:43][O:42][N:41]=4)=[O:20])[C:14]=3[N:15]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccon1
Reactant: O=C(O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccon1)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoic acid (50 mg, 0.096 mmol) in SOCl2 (1 mL) was heated at 70° C. for 1 h. The reaction mixture was concentrated, dissolved in CH2Cl2 (2 mL), and treated with 3-aminoisoxazole (2.97 mg, 0.035 mmol). The reaction mixture was stirred at room temperature for 1 h, concentrated, and purified by flash column chromatography (silica gel, 0 30% Hex/EtOAc) to give the title compound 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-isoxazol-3-yl-benzamide as a white solid. 1H NMR (CDCl3□ (ppm) 9.94 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.72 (t, 1H), 7.49 (d, 2H), 7.45 (d, 2H), 7.39 (t, 2H), 7.35 7.29 (m, 5H), 7.25 (br s, 1H), 7.14 (d, 2H); HPLC-MS calculated for C30H20ClN5O2 (M+H+): 585.1. Found: 585.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[F:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[CH2:24][C:25]1[CH:29]=[CH:28][NH:27][C:26]=1[CH2:30]O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:30][C:26]1[NH:27][CH:28]=[CH:29][C:25]=1[CH2:24][C:23]1[CH:32]=[CH:33][CH:34]=[C:21]([F:20])[CH:22]=1)=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Reactant: OCc1[nH]ccc1Cc1cccc(F)c1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1[nH]ccc1Cc1cccc(F)c1

Procedure:
The acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with 3-(3-fluorobenzyl)-pyrrolylmethyl alcohol using the procedure of Example 1 to give 3-(3-fluorobenzyl)-pyrrolylmethyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.O.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]>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([C:27]3[CH:28]=[N:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(C(F)(F)F)nc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
A mixture of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (1.5 g, 3.1 mmol), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (705 mg, 3.7 mmol), Pd(dppf)Cl2 (245 mg, 0.3 mmol) and Na2CO3 (985 mg, 9.3 mmol) in dioxane/H2O (20 mL/4 mL) was stirred at 80° C. for 6 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (PE:EA=1:1) to give the product of 5-bromo-N-methyl-6-(N-methylmethylsulfonamido)-2-(6-(trifluoromethyl)pyridin-3-yl)benzofuran-3-carboxamide (1.4 g, yield: 90%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.24 (s, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.56 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 3.23 (s, 3H), 3.22 (s, 3H), 2.85 (d, J=4.4 Hz, 3H). MS (M+H)+: 506/508.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][CH2:8][C:9](=O)[NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C1CCC2=C(CCc3cc(F)ccc32)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)CCC1=C2CCCN1
Reaction time: 2.5 h

Procedure:
6.20 g of 8-fluoro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one are added portionwise under nitrogen within 35 minutes at 20° to 25° to a stirred suspension of 2.17 g of lithium aluminum hydride in 60 ml of dry tetrahydrofuran. The reaction mixture is boiled for 150 minutes under reflux and then treated at 0° to 10° with 7.0 ml of 6.5N sodium hydroxide solution. The mixture is filtered, rinsed several times with 20 ml of tetrahydrofuran each time and the solvent is distilled in a vacuum. The thus-obtained 8-fluoro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline obtained is processed directly.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=O)[CH3:19])[CH2:13]1.O>C1COCC1>[CH2:18]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][C:10]2[CH:21]=[CH:22][CH:23]=[C:8]([F:7])[CH:9]=2)[CH2:13]1)[CH3:19]
Reactant: CC(=O)N1CCCC(Cc2cccc(F)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCCC(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A solution of lithium aluminium hydride (2M in THF, 2.8 mL) was added dropwise to a solution of 1-[3-(3-fluorobenzyl)piperidin-1-yl]ethanone (Intermediate 224, 0.66 g) in anhydrous THF (20 mL) at 0° C. under argon. The mixture was stirred for 30 minutes then allowed to warm to room temperature and stirred for 2 hours. The mixture was recooled to 0° C. and water was added. The mixture was extracted with ether, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 1-ethyl-3-(3-fluorobenzyl)piperidine (0.535 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][C:2]1=[O:12].[H-].[Na+].[CH2:15](I)[CH3:16]>CC(N(C)C)=O>[CH2:15]([O:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:12])[CH:3]=1)[CH3:16]
Reactant: CCI
Reactant: O=C1CC(=O)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 6 g. of quinoline-2,4-dione in 50 ml. of dimethylacetamide is added 1.6 g. of sodium hydride (56% in mineral oil, pentane washed). The mixture is then stirred at room temperature for 90 minutes and 6 g. of ethyliodide is added and the resulting mixture is heated briefly at 35° C. followed by stirring at ambient temperature for 18 hours. The precipitate which forms is recovered by filtering and the filtrate is poured into 200 ml. of water and the resulting precipitate also recovered by filtering and dried. The two filter cakes above obtained are combined and crystallized from methanol to obtain 4-ethoxyquinolin-2(1H)-one, m.p. 223°-226° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:17]([OH:19])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc2ccccc2n1-c1cccc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a mixture of 1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethanone (0.27 g, 1.1 mmol) in methanol (6 mL) was added sodium tetrahydroborate (41 mg, 1.1 mmol). The reaction was stirred at room temperature for 1 hour, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give title compound (0.26 g). The crude product was used directly in the next step. LCMS calculated for C16H13FN(M-OH)+: m/z=238.1. Found: 238.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(#N)C>[CH:11]([N:8]1[C:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH:10]=[N:9]1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C(C)C
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(N2CCN(C)CC2)nc2c1cnn2C(C)C
Yield: 100.2 %

Procedure:
To a stirred solution of ethyl 6-bromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.3 g, 0.964 mmol) in acetonitrile (10 mL), K2CO3 (0.26 g, 1.93 mmol) and 1-methylpiperazine (0.289 g, 2.892 mmol) was added. The reaction mixture was refluxed for 3 h. On completion of reaction, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to obtain the desired intermediate (0.32 g, 94.9%).