Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C1C=CC=CC=1>[CH3:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[N:1][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=1)=[O:20]
Reactant: CN1CCCCC1=N
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to the free base in benzene in the usual manner. After drying over K 2 CO 3 and filtering, a benzene solution of 0.05 mole of p-nitrophenylisocyanate is added dropwise with stirring. After addition is complete, further stirring is continued for about 6 hours at room temperature. The benzene is evaporated in vacuo and the solid residue is recrystallized from methanol to give the product, 1-(1-methyl-2-piperidylidene)-3-(4-nitrophenyl)urea.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[OH:1][CH2:2][C:3]([C:4]1[O:6][N:63]=[C:62]([NH:61][C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([C:45]3[C:44](=[O:66])[N:43]([CH3:42])[C:52]4[C:47]([CH:46]=3)=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=4)[CH:55]=2)[N:65]=1)([CH3:8])[CH3:7]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CC(C)(CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)(C)CO)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (88 mg, 0.7 mmol) in DMF (5 mL) were added DIPEA (0.26 mL, 1.5 mmol) and HATU (0.21 g, 0.7 mmol). After stirring at rt for 15 min, 17 (0.25 g, 0.7 mmol) was added as a solution in DMF (2 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 2 h. Subsequently the reaction was cooled to rt, partitioned with EtOAc (30 mL) and 5% aq NaHCO3 (20 mL). The aqueous layer was extracted with fresh EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and reduced to dryness. The crude material was purified by flash column chromatography on silica with DCM/4% MeOH as eluant to give 3-(5-(5-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A35) as a clear glassy solid. 1H NMR (400 MHz, d6-DMSO) 9.86 (s, 1H), 8.81 (s, 1H), 7.93 (s, 1H), 7.43 (s, 1H), 7.37 (dd, J=8, 2 Hz, 1H), 7.28 (d, J=2 Hz, 1H), 7.21 (d, J=8 Hz, 2H), 5.10 (t, J=5.5 Hz, 1H), 3.65 (s, 3H), 3.55, (d, J=5.5 Hz, 1H) 2.61 (s, 3H), 2.07 (s, 3H), 1.31 (s, 6H). MS m/z 420.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C1COCC1.C(OCC)(=O)C>[F:16][CH:15]([F:17])[O:14][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-(difluoromethoxy)propanoic acid (780 mg, 3.05 mmol) and triethylamine (924 mg, 9.15 mmol) in THF (15 mL) at −78° C., isobutyl chloroformate (417.7 mg, 3.05 mmol) was added dropwise. After 30 minutes, (4-fluorobenzyl)amine (458 mg, 3.0 mmol) was added and the reaction mixture allowed to warm up to room temperature. The mixture was then diluted with ethyl acetate and washed with water, 0.5N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated, and triturated with hexanes (1:3) to give tert-butyl {(1R)-1-[(difluoromethoxy)methyl]-2-[(4-fluorobenzyl)amino]-2-oxoethyl}carbamate (870 mg, 78.7%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.23 (dd, 2H), 7.03 (t, 2H), 6.60 (b, 1H), 6.23 (wt, 1H), 5.24 (w, 1H), 4.3-4.51 (m, 4H), 4.02 (dd, 1H) and 1.45 (s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4OS(C(F)(F)F)(=O)=O)[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li+].[Cl-].[C:38](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:39]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:24]([F:25])([F:27])[C:21]1[CH:22]=[CH:23][C:18]([C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[CH:13]=2)=[C:19]([CH:38]=[CH2:39])[CH:20]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=S(=O)(Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 25 °C

Procedure:
To a solution of trifluoromethanesulfonic acid 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl ester, (Example 192(a)), (600 mg, 1.2 mmol) in dioxane (6.0 mL) was added vinyltributylstannate (370 μL, 1.6 mmol, Fluka), LiCl (150 mg, 3.5 mmol, Aldrich), Pd(PPh3)4 (27 mg, 0.02 mmol, Strem) and a few crystals of 2,6-di-tert-butyl-4-methylphenol (Aldrich). The reaction mixture was stirred at reflux for 21 h. The resulting mixture was allowed to cool to room temperature and concentrated in vacuum. Purification by silica gel chromatography (1% MeOH/CH2Cl2) provided the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 394 (M+1).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([OH:21])=O)[CH2:17][C:6]=2[CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]2[C:37](=[O:46])[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:32][CH2:31]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:21])[N:30]3[CH2:31][CH2:32][CH:33]([C:36]4[C:37](=[O:46])[NH:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:34][CH2:35]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Yield: 41 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (100 mg, 0.23 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-one (55 mg, 0.24 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 41% yield. MS m/e (M+H)+=595.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 11.76 (s, 1H), 8.30 (d, J=5.19, 2H), 8.23 (s, 1H), 7.69 (d, J=19.84, 1H), 7.62 (m, 1H), 7.44 (m, 1H), 7.28 (d, J=7.93, 1H), 7.21 (s, 1H), 7.14 (m, 3H), 5.40 (d, J=17.09, 1H), 4.65 (m, 3H), 4.13 (d, J=13.43, 1H), 4.01 (m, 1H), 3.17 (d, J=14.95, 2H), 3.04 (m, 2H), 2.94 (m, 1H), 2.66 (m, 1H), 2.45 (m, 2H), 1.93 (d, J=11.60, 1H), 1.85 (d, J=12.82, 1H), 1.56 (m, 1H), 1.41 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1C[C@H](O)C[C@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@H](O)C[C@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using (3R,5S)-5-hydroxymethylpyrrolidin-3-ol described in Collect. Czech. Chem. Commun., vol. 61, pp. S234-S237 (1996), 3-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: FC(F)(F)S(OC1C=CC2C(=CC=CC=2)C=1[N+]([O-])=O)(=O)=O.C(OC(=O)NC1C=CC=C(N)C=1)(C)(C)C.CC1C(C)=CC=CC=1C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1F)=O.[NH2:72][CH2:73][C:74]1C=[CH:78][C:77]([N:80]2[C:86](=[O:87])[CH2:85][C:84](=[O:88])[NH:83][C:82]3[C:89]4[C:94]([CH:95]=[CH:96][C:81]2=3)=[CH:93][CH:92]=[CH:91][CH:90]=4)=[CH:76][CH:75]=1>>[NH2:72][C:73]1[CH:78]=[C:77]([N:80]2[C:86](=[O:87])[CH2:85][C:84](=[O:88])[NH:83][C:82]3[C:89]4[C:94]([CH:95]=[CH:96][C:81]2=3)=[CH:93][CH:92]=[CH:91][CH:90]=4)[CH:76]=[CH:75][CH:74]=1
Reactant: NCc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: Cc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2F)c1C
Agent: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Product: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Yield: 17 %

Procedure:
By using 1-nitro-2-naphthyl trifluoromethanesulfonate (5.94 g, 18.5 mmol), and tert-butyl(3-aminophenyl)carbamate, the title compound (1.02 g, yield 17%) was obtained as brown crystals in the same manner as that of Example 1, (1), (2) and (3).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:19]=[N:20][NH:21][C:22]=2[CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])O)[N:9]=[N:8]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:34]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:19]=[N:20][NH:21][C:22]=2[CH2:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[N:9]=[N:8]1
Reactant: OC(c1ccccc1Cl)c1[nH]nnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(Cn2nnc(-c3nn[nH]c3Cc3ccccc3Cl)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Dissolve [1′-(3,5-bis-trifluoromethyl-benzyl)-5′-phenyl-1H,1′H-[4,4′]bi[[1,2,3]triazolyl]-5-yl]-(2-chloro-phenyl)-methanol (38 mg, 0.066 mmol) and 1.5 mL CH2Cl2. Carefully add triethylsilane (23 mg, 31.4 μL, 0.197 mmol). Cool to 0° C. and add trifluoroacetic acid (452 mg, 305 μL, 3.96 mmol) and stir. After 15 hours, pour into 10 mL of (saturated aqueous NaHCO3) and 20 mL of CH2Cl2. Extract 3 times with CH2Cl2 and 1 time with EtOAc. Combine the organics, dry over MgSO4 and filter and concentrate. Apply the mixture to a 2 mm chromatotron plate with CH2Cl2 and EtOAc and elute with a 100 mL of Hexanes, and then 200 mL each of of 10:90 EtOAc/Hexanes, 20:80 EtOAc/Hexanes, 30:70 EtOAc/Hexanes, 50:50 Hexanes/EtOAc to provide the title compound. Exact Mass 562.1: mass spectrum (IS): m/z=563.1 (M+1), 561.1 (M−1); 1H NMR (250 MHz, CDCl3) 7.72 (s, 1H), 7.42-7.28 (m, 5H), 7.24 (m, 1H), 7.16-6.97 (m, 6H), 5.52 (s, 2H), 4.37 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:24])([CH3:23])[C:9]([NH:11][NH:12][C:13](=[S:22])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)=[CH:4][C:3]=1[O:25][CH3:26].Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13]([SH:22])=[N:12][N:11]=2)([CH3:24])[CH3:23])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(C(C)(C)C(=O)NNC(=S)Nc2ccc(F)cc2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(C)(C)c2nnc(S)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 5 °C
Yield: 99.2 %

Procedure:
A solution of 2-(2-(4-chloro-3-methoxyphenyl)-2-methylpropanoyl)-N-(4-fluorophenyl)-hydrazine carbothioamide (8.13 g, 0.02 mol) in 3N NaOH (270 mL) was heated at reflux 4 h with mechanical stirring. The reaction mixture was cooled to 5° C. and acidified with 5N HCl to pH=4. The resulting whited solids were collected by filtration, washed with Et2O and dried to give the title compound (7.5 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.21 (d, 1H), 6.95-6.91 (t, 2H), 6.54 (d, 1H), 6.52-6.49 (dd, 1H), 6.45-6.41 (m, 2H), 3.67 (s, 3H), 1.45 (s, 6H).
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH2:6][CH:5]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[Cl:23])[NH:19][CH:18]=[C:17]3[C:24]([O:26]C)=[O:25])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[CH2:7][CH2:6][CH:5]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[Cl:23])[NH:19][CH:18]=[C:17]3[C:24]([OH:26])=[O:25])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN4C(C)=O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCC1c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 7.4 %

Procedure:
To a solution of methyl 5-[4-(1-acetylazetidin-2-yl)phenyl]-6-chloro-1H-indole-3-carboxylate (40 mg, 0.11 mmol) in methanol (8 mL) was added 1.0 M aq. NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (3 mg, 7% yield) as a white solid.
Reaction SMILES: [C:1]([P:9](=[O:14])([O:12]C)[O:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+:16]>CC(CC)=O>[C:1]([P:9](=[O:12])([O-:14])[O:10][CH3:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:16]
Reactant: COP(=O)(OC)C(=O)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COP(=O)([O-])C(=O)c1ccccc1

Procedure:
Dimethyl benzoylphosphonate (12.8 g, 0.06 mol) and sodium iodide (9.0 g, 0.06 mol) were dissolved in ethyl methyl ketone (160 ml) and the solution stirred and refluxed for 16 hours. There was evidence of a precipitation after about 10 minutes refluxing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH3:34])=[O:6]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (93 mg, 0.238 mmol) and N-(2-methoxyethyl)methylamine (31 μl, 0.286 mmol). MS (ESI) m/z: Calculated: 461.2; Observed: 462.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Br)cc(F)c3O2)cc1
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4C)cc(F)c3O2)cc1

Procedure:
Treatment of 4-bromo-2-fluorophenol (25.0 g, 130.9 mmol) with potassium carbonate (72.35 g, 523.53 mmol) and allyl bromide (19.00 g, 157.06 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-4-bromo-6-fluorophenol. Treatment of 2-allyl-4-bromo-6-fluorophenol (25.6 g, 110.8 mmol) with 3-chloroperoxybenzoic acid (57.36 g, 332.38 mmol, 77%) followed by potassium carbonate (38.28 g, 277.0 mmol) generally according to the procedure described for Intermediate 9 afforded 19.1 g (70%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (18.61 g, 75.3 mmol) with p-toluenesulfonyl chloride (17.22 g, 90.34 mmol) generally according to the procedure described for Intermediate 10 gave 22.6 g (75%) of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-fluoro-5-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.25 mmol) and 2-methylphenylboronic acid (0.254 g, 1.87 mmol) generally according to the procedure described for Intermediate 35 afforded 0.282 g, (55%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (99%) of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.30 g, 3.0 mmol) according to the procedure described in Example 154 afforded 0.038 g (22%) of (±)-([7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]amine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]1[N:42]([C:41]2[CH:43]=[CH:44][C:38]([F:37])=[CH:39][CH:40]=2)[C:18](=[O:20])[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1nc2ccccc2c(=O)n1-c1ccc(F)cc1)OCc1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of the benzoic acid (2) (180 mg, 0.55 mmol) in tetrahydrofuran (6 mL) was added 1,1′-carbonyldiimidazole (98 mg, 0.60 mmol). After a period of 2 h, 4-fluoroaniline (61 mg, 0.55 mmol) in tetrahydrofuran (1.5 mL) was added and the mixture was stirred at 75° C. overnight. The tetrahydrofuran was removed in vacuo and the residue was redissolved in ethyl acetate, washed with 10% aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and concentrated to give an oily residue which was subjected to silica-gel column chromatography [eluent: Ethyl acetate:Hexane, 20:80, ν/ν->60:40, ν/ν] to give the title quinazolinone (3) (0.11 g, 50%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(OCC)(=O)C.O>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[N:11]=[C:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(N2CCCC2)nc1Cl
Reaction time: 1 h

Procedure:
To a solution of 1.5 g of methyl 2,6-dichloro-5-fluoronicotinate in 15 mL of N,N-dimethylformamide, 0.93 mL of triethylamine was added at room temperature, and thereto was dropped 0.56 mL of pyrrolidine. The mixture was stirred at the same temperature for 1 hour, 56 μL of pyrrolidine was further added, and the mixture was stirred for 50 minutes. After leaving overnight, ethyl acetate and water were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.7 g of methyl 2-chloro-5-fluoro-6-(pyrrolidin-1-yl)nicotinate as a white solid.
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=2)[CH2:22]1)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].Cl.Cl[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:9][CH:10]=1)[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Product: CCN(Cc1ccc(OCCCN2CCCCC2)cc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 68.7 %

Procedure:
Synthesized from N-ethyl-4-hydroxy-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (500 mg) and 1-(3-chloropropyl)piperidine hydrochloride (298 mg) according to an analogous synthetic method to Example 368, the title compound (410 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][Si](C(C)(C)C)(C)C)[C@@H:14]([O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@@:12]3([CH3:36])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.F.F.F.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([O:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@@:12]3([CH3:36])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCCCCCC(=O)O[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc3c(N)ncnc32)[C@]1(C)O
Agent: F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCC(=O)O[C@@H]1[C@@H](CO)O[C@@H](n2ccc3c(N)ncnc32)[C@]1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of the compound from Step J (230 mg, 0.44 mmol) in anhydrous THF (5 mL), was added triethylamine (300 μL, 2.14 mmol) and triethylamine trihydrofluoride (750 μL, 4.5 mmol). The solution was stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (3×10 mL) and water (10 mL). After drying the organic layer over anhydrous sodium sulfate and filtration, the solvent was evaporated. The resulting oil was purified on a silica gel column eluting with 1:1 acetone/CH2Cl2 followed by 10% MeOH in CH2Cl2. The appropriate fractions were concentrated and lyophilized to afford the title compound as a colorless powder (90 mg).