Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][F:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.[CH3:14][N:15]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[F:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=[C:2]1[C:30]#[C:29][C:26]1[CH:25]=[CH:24][C:23]([N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:28][CH:27]=1
Reactant: C#Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Reactant: FCCn1c(Br)nc2ccccc21
Product: CN(C(=O)OC(C)(C)C)c1ccc(C#Cc2nc3ccccc3n2CCF)cc1
Yield: 35.3 %

Procedure:
T534 was prepared using general procedure B from 2-bromo-1-(2-fluoroethyl)-1H-benzo[d]imidazole and tert-butyl methyl-4-(ethynyl)phenylcarbamate. Reaction was performed on a 53 mgs scale of 2-bromo-1-(2-fluoroethyl)-1H-benzo[d]imidazole. The crude product was purified by ISCO column to afford tert-butyl 4-((1-(2-fluoroethyl)-1H-benzo[d]imidazol-2-yl)ethynyl)phenyl(methyl)carbamate (0.03 g, 35.3%). It was dissolved in acetonitrile (0.5 mL). To this solution was added a solution of 20% sulfuric acid (1.5 mL, 5.63 mmol). The resulting mixture was stirred at room temperature for 20 minutes, diluted with water (2.0 mL) and purified by preparative HPLC to afford T534 as TFA salt (0.004 g, 12.88%). 1H NMR (400 MHz, CD3CN) δ 7.81-7.79 (m, 1H), 7.67-7.65 (m, 1H), 7.52-7.48 (m, 4H), 6.66-6.64 (m, 2H), 4.95-4.93 (m, 1H), 4.83-4.478 (m, 2H), 4.74-4.73 (m, 1H), 2.82 (s, 3H); MS (ESI): 294.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11]O.N1C=CC=CC=1.S(Cl)([Cl:21])=O.O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][Cl:21]
Reactant: Nc1c(NCCCO)c(=O)c1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: Nc1c(NCCCCl)c(=O)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 1-amino-2-(3-hydroxypropylamino)cyclobut-1-ene-3,4-dione (1.0 g) and pyridine (0.5 ml) in chloroform (100 ml) was cooled to 0° C. To this was added dropwise thionyl chloride (4.38 g) in chloroform (30 ml) and the reaction mixture was stirred overnight at room temperature. There was solid remaining so more thionyl chloride (4.38 g) was added, the solid slowly dissolving, and the reaction mixture was left to stand for 60 hours. The mixture was evaporated under reduced pressure to afford an oily residue, which on the addition of water gave a solid which was collected by filtration and dried to give the title compound (0.73 g); δppm 2.0 (2H, m), 3.5-3.8 (4H, m), 7.45 (broad m); m/e 190, 188, 152, 134, 132, 97, 96, 69.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:37]=[C:36]3[C:31]([CH:32]=[CH:33][CH:34]=[C:35]3[C:38]([O:40][CH3:41])=[O:39])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[CH:33][CH:34]=[C:35]4[C:38]([O:40][CH3:41])=[O:39])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1cccc2ccc(-c3ccc(O)cc3)cc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Temperature: 80 °C
Yield: 57.7 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.050 g, 0.16 mmol), methyl 7-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.045 g, 0.16 mmol), triphenyl phosphine (0.042 g, 0.16 mmol) and diisopropyl azodicarboxylate (0.043 mL, 0.16 mmol) in dichloromethane (1.6 mL) was placed in microwave reaction tube and heated to 80° C. for 20 minutes. The solution was concentrated and the residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.053 g, 58%). 1H NMR (DMSO-d6): 8.99 (s, 1H), 8.20 (d, J=8 Hz, 1H), 8.16 (d, J=7 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.90 (d, J=9 Hz, 1H), 7.74 (d, J=8 Hz, 2H), 7.59-7.56 (m, 1H), 7.41 (d, J=8 Hz, 2H), 7.26-7.24 (m, 1H), 7.16 (d, J=8 Hz, 2H), 4.99 (s, 2H), 3.94 (s, 3H), 3.39-3.20 (2m, overlapping H2O, total 3H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 574 (M+H)+.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:25]([CH2:26][NH:27][CH2:28][CH3:29])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:9]=1)[CH3:4].C(N(C(C)C)CC)(C)C.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:25]([CH2:26][N:27]([C:43]([CH:40]3[CH2:42][CH2:41]3)=[O:44])[CH2:28][CH3:29])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:9]=1)[CH3:4]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc2ccccc2nc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)C2CC2)c1
Reaction time: 0.08 h

Procedure:
[3-(3-Ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, dihydrochloride (0.40 g, 0.89 mmol) and diisopropylethylamine (1.0 mL, 5.74 mmol) were combined in CH2Cl2 (5 mL) and stirred for 5 minutes. Cyclopropanecarbonyl chloride (0.09 mL, 0.99 mmol) was added, and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-75% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:16]O>>[SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Mercaptobenzoic acid (10.0 g) was suspended in methanol (310 mL), added with sulfuric acid (0.3 mL), and stirred for 24 hours under reflux with heating. After cooling to room temperature, the solvent was evaporated under reduced pressure and water was added to residues. After adjusting to pH 8 by using a saturated aqueous solution of sodium hydrogen carbonate, it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After distilling the solvent under reduced pressure, the residues were purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].C(CC(O)=O)C.[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:29](=[O:39])[C:30](=[N:37][OH:38])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:26](=[O:40])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13].[N-]=C=O>>[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:29](=[O:39])[C:30](=[N:37][O:38][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:26](=[O:40])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24])(=[O:14])[CH3:13]
Reactant: CCN=C=O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Agent: [N-]=C=O
Solvent: CCCC(=O)O
Product: CCNC(=O)ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To ethyl isocyanate (5 ml.) was added 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid ethyl acetate solvate (syn-isomer) (0.9 g.) and the mixture stirred for one hour at room temperature. Two further portions of the isocyanate (5 ml.) were added, over a period of two hours. The mixture was then allowed to stand for one hour, and poured into petroleum (b.p. 40°-60°; 250 ml.) and the resulting precipitate collected, washed thoroughly with petroleum and dried. The solid was dissolved in ethyl acetate and extracted into sodium bicarbonate solution; the bicarbonate solution was then washed with ethyl acetate, acidified (2 N-hydrochloric acid) and extracted with ethyl acetate. The combined extracts were dried and concentrated, and the concentrate (ca. 5 ml.) added dropwise to petroleum spirit with vigorous stirring. The precipitate formed was filtered and dried, giving the title acid (0.4 g.; 47%), [α]D +50° (c 0.85, DMSO), λmax. (pH 6 buffer) 257.5 nm (ε 21,200), νmax. (Nujol) 1782 (β-lactam), 1675 and 1520 cm.-1 (CONH), τ (DMSO-d6) values include 0.04 (doublet J 8 Hz; NH), 2.0-2.6 (multiplet; aromatic protons), 6.7-7.1 (multiplet; NHCH2CH3) and 8.89 (triplet, J 9 Hz; CH2CH3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.2 g (8.1 mmol) of 4-formylbenzeneboronic acid and 1.1 g (8.1 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 4 hours whereupon 0.3 g (2.0 mmol) of 4-formylbenzeneboronic acid and 0.1 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and heating continued for 16 hours. To this solution was added 5 mL of water and heating continued for 1 hour. The mixture was then cooled to ambient temperature and 10 mL of water was added. The organic portion was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (50% ethyl acetate/hexane) afforded a solid which was recrystallized from bromobutane/ethyl acetate, filtered and dried in vacuo at 60° C. to afford 0.5 g (32%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.Cl.[OH:23][CH:24]1[CH2:27][NH:26][CH2:25]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([N:26]2[CH2:27][CH:24]([OH:23])[CH2:25]2)=[O:21])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2
Reactant: OC1CNC1
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F)N1CC(O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (70 mg, 0.176 mmol) and 3-hydroxyazetidine hydrochloride (23 mg, 0.21 mmol) in DMF (1 mL) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate then water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in cyclohexane to give the title compound as a pale tan solid (39 mg, 49%). LCMS (Method A): RT=8.23 min, [M+H]+=453. 1H NMR (DMSO-d6, 400 MHz) 13.17 (1 H, s), 9.55 (1 H, s), 7.63 (1 H, dd, J=10.47, 1.94 Hz), 7.41-7.37 (1 H, m), 7.37 (1 H, s), 7.32 (1 H, d, J=8.69 Hz), 7.05-7.00 (1 H, m), 6.92-6.82 (1 H, m), 5.67 (1 H, d, J=6.13 Hz), 4.44-4.37 (1 H, m), 4.24 (2 H, br, s), 3.83 (2 H, br, s).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C@@H:19]1[C@@H:23]([CH2:24][OH:25])[O:22][C@@H:21](N2C=CC(=O)NC2=O)[CH2:20]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[CH2:1]([S:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C@@H:21]1[O:22][C@H:23]([CH2:24][OH:25])[C@@H:19]([F:18])[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: c1ccc(CSc2ncnc3[nH]cnc23)cc1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(SCc4ccccc4)ncnc32)C[C@@H]1F
Temperature: 45 °C
Reaction time: 72 h
Yield: 81.3 %

Procedure:
6-Benzylmercapto-9H-purine (0.49 g, 2.0 mmoles, Sigma Chemical Company) and 2',3'-dideoxy-3'-fluorouridine (0.32 g, 1.4 mmoles) were suspended in potassium phosphate buffer (10 mM) 100 ml), pH 6.8, containing 0.04% potassium azide. Purified purine nucleoside phosphorylase (1070 I.U.) and thymidine phosphorylase (400 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) were added to the reaction mixture and the suspension stirred at 45° C. After 3 days, additional purine nucleoside phosphorylase (10,700 I.U.) and thymidine phosphorylase (4000 I.U.) were added. Four days later, methanol was added to the reaction mixture to precipitate protein. The protein was removed by filtration and the filtrate applied to a series of coupled columns. The first column contained AG1 resin (2.5×10 cm, OH- form) and the second column contained XAD resin (2.5×20 cm). The columns were washed with water 300 ml and the product removed with methanol. Product fractions were pooled and solvent was removed in vacuo. The residue was flash chromatographed on silica gel (2.5×20 cm) using chloroform:methanol (199:1). Solvent was removed and lyophilization yielded 6-benzylmercapto-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (0.41 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][CH2:21][NH:22][CH3:23])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[C:25]([OH:28])(=O)[CH3:26]>>[OH:24][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][CH2:21][N:22]([CH3:23])[C:25](=[O:28])[CH3:26])[N:12]=[CH:11][N:10]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: CC(=O)O
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 2-methyl-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol (obtained as described in Example 3, preparation of starting materials) to give N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide as a light brown solid in 100% yield; NMR spectrum (DMSO-d6) 1.90 (s, 3H), 2.16 (s, 3H), 3.02 (s, 3H), 3.85 (t, 2H), 4.45 (t, 2H), 6.82 (d, 1H), 7.18 (dd, 1H), 7.25 (d, 1H), 7.34 (m, 2H), 7.92 (t, 1H), 8.65 (s, 1H), 9.45 (s, 1H), 10.52 (s, 1H); Mass spectrum MH+ 367.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[S:13])[NH:8]3.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[N:8]3
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1nc2cccc3[nH]c(=S)c1n23
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3nc(SCCCCN4C(=O)c5ccccc5C4=O)c1n23
Temperature: 100 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A mixture of 5.68 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]indene-2-thione, 8.47 g (30 mmol) of N-(4-bromobutyl)phthalimide and 6.27 ml (45 mmol) of triethylamine in 150 ml of DMF was stirred for 2 hours at 100° C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract solution was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from chloroform-ethanol to give 7.39 g of the desired compound (63.1%, pale brown solid)
Reaction SMILES: I[CH:2]([CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[Br:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:16]=[N+:17]=[N-:18].[Na+].C(O)C.N(C(CC(F)(F)C(F)(F)Br)C([O-])=O)=[N+]=[N-]>O>[N:16]([CH:2]([CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[Br:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(I)CC(F)(F)C(F)(F)Br
Agent: [N-]=[N+]=NC(CC(F)(F)C(F)(F)Br)C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC(F)(F)C(F)(F)Br)N=[N+]=[N-]
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Subsequently, 9.7 g (0.024 mol) of ethyl 2-iodo-4,4,5,5-tetrafluoro-5-bromopentanoate and 2.73 g (0.042 mol) of sodium azide were added to 40 ml of 80% ethanol and were refluxed while under stirring at an elevated temperature for one hour. Then water was added to the resultant mixture and 2-azido-4,4,5,5-tetrafluoro-5-bromopentanoate was extracted with ether, whereafter the ether was removed by drying. The residual liquid was vacuum distilled to afford 4.54 g (0.014 mol, yield of 60%) of ethyl 2-azido-4,4,5,5-tetrafluoro-5-bromopentanoate having b.p. 78° to 79° C./4 mm, nD20 1.4291, d420 1.564, νN3 2120 cm-1 and νC=O 1746 cm-1.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN1CCOCC1>C(Cl)Cl>[C:28]1([NH:34][C:35]([N:7]2[CH2:6][CH2:5][C:4]([NH:10][C:11]([CH:13]([NH:19][C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])([C:2]#[N:3])[CH2:9][CH2:8]2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(C(=O)Nc2ccccc2)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and phenyl isocyanate in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)C.O[Li].O.OP(O)(O)=O>O1CCOCC1.O.CCOCC>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: O=P(O)(O)O
Agent: [Li]O
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Temperature: 45 °C
Yield: 79.2 %

Procedure:
To a solution of (E)-ethyl-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-prop-2-en-oate (970 mg, 3.2 mmol) in 3 mL of 1,4-dioxane was added a solution of LiOH·H2O (156 mg, 3.8 mmol) in 3 mL of H2O. The resulting mixture was heated at 80° C. for 2 hr and 45° C. for 16 hr. The resulting solution was diluted with ether and poured into 1M H3PO4. The aqueous layer was extracted with ethyl acetate (2×), washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Silica gel chromatography (95:5, CH2Cl:methanol) provided (E)-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-prop-2-enoic acid as a colorless solid (700 mg, 79%). Anal. Calcd for C16H20O4 : C, 69.55; H, 7.29. Found: C, 69.39; H, 7.29.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]3([C:25]([F:28])([F:27])[F:26])[CH2:24][CH2:23]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:45]=[C:46]([NH:47][C:13]([NH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:22]3([C:25]([F:26])([F:28])[F:27])[CH2:24][CH2:23]3)[CH:10]=2)=[O:21])[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5(C(F)(F)F)CC5)nn4-c4ccccc4)c3)c2cc1OC
Yield: 71 %

Procedure:
The title compound was prepared from phenyl 1-phenyl-3-(1-(trifluoromethyl) cyclopropyl)-1H-pyrazol-5-ylcarbamate described in Example 137A (129 mg, 0.33 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline described in Example 113A (100 mg, 0.33 mmol) using the procedure described in Example 115C. The crude product was purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (139 mg, 0.24 mmol, 71%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 7.63-7.51 (m, 6H), 7.48 (d, 1H), 7.39 (s, 1H), 7.37 (t, 1H), 7.17 (d, 1H), 6.93 (d, 1H), 6.55 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.31 (d, 4H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][CH2:17][OH:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[OH-].[Na+].[CH2:21](Br)[C:22]#[CH:23]>ClCCl.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:23]([O:18][CH2:17][CH2:16][CH2:15][N:3]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=[C:2]1[CH3:1])[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: Cc1nc2cnc3ccccc3c2n1CCCO
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOCCCn1c(C)nc2cnc3ccccc3c21
Reaction time: 0.08 h
Yield: 33 %

Procedure:
To 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-propanol (12.2 g, 50.56 mmol) dissolved in dichloromethane (180 mL) was added sodium hydroxide (180 mL of 50%) with mechanical stirring. Benzyltrimethylammonium chloride (1.88 g, 10.11 mmol) was added to the resulting suspension, and after stirring for 5 minutes, propargyl bromide (17 mL of 80% in toluene, 141.8 mmol) was added. The resulting reaction mixture was allowed to stir at ambient temperature. After 2 hours, TLC monitoring indicated 50% completion, and after 4.5 hours HPLC monitoring indicated 20% starting material remaining. More propargyl bromide (5 mL of 80% in toluene, 40.51 mmol) was added, and the resulting reaction mixture was allowed to stir at ambient temperature for 64.5 hours. The layers were separated, and the organic layer was washed with water (3×) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting dark oil was dissolved in dichloromethane and again extracted with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting dark oil was purified by silica gel column chromatography using 98/2 dichloromethane/methanol as the eluant. After removing the solvent from the collected fractions, 5.880 g of pure (by HNMR analysis) product was obtained. This material was recrystallized from ethyl acetate/hexane to provide 4.658 g of brown crystals.