Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)#[CH:12].N>>[F:19][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1cccc(F)c1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: Fc1cccc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-ethynyl-3-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.19-7.33 (m, 1H), 7.48 (s, 1 H), 7.58 (td, J=8.1, 5.8 Hz, 1H), 7.69 (dt, J=9.6, 2.2 Hz, 1H), 7.77 (dt, J=8.0, 1.1 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.4, 1.7 Hz, 1H), 9.29 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:43])[NH:12][C:13]2[CH:14]=[C:15]([CH:40]=[CH:41][CH:42]=2)[O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH2:30][CH:31]4[CH2:36][CH2:35][N:34](C([O-])=O)[CH2:33][CH2:32]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:12][C:13]2[CH:42]=[CH:41][CH:40]=[C:15]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH2:30][CH:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:14]=2)=[O:43])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)ncnc2cc1OCC1CCN(C(=O)[O-])CC1
Agent: Cl
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of 4-((4-(3-(3-(3-tert-butylisoxazol-5-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)methyl)piperidine-1-carboxylate (49 mg, 0.062 mmol) in dichloromethane (0.31 mL) was added hydrochloric acid (0.31 mL, 4M in dioxane) and the mixture stirred at room temperature for 30 minutes. The solid was filtered off, dissolved in methanol and concentrated under reduced pressure. The residue was taken in ethyl acetate and a saturated solution of sodium bicarbonate was added until the solution became basic. The solid was filtered off, washed thoroughly with water and dried to afford 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yloxy)phenyl)urea as a white solid (23.31 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 10.10 (bs, 1H), 9.65 (bs, 1H), 8.56 (s, 1H), 7.61-7.21 (m, 5H), 6.95 (d, 1H), 6.56 (s, 1H), 4.25-3.90 (m, 6H), 3.00 (d, 2H), 2.45 (d, 2H), 2.20-1.79 (m, 1H), 1.78-1.51 (m, 4H), 1.25 (s, 9H); LC-MS (ESI) m/z 547 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[CH:16][CH:15]=1>>[C:9]1([C@H:20]2[C@H:20]([C:17]3[CH:16]=[CH:15][C:14]([Br:13])=[CH:19][CH:18]=3)[C:21](=[O:22])[NH:23][C:21]2=[O:22])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(Br)cc1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(Br)cc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(4-bromophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 4-bromophenylacetamide. Yield 33.1 mg, 8.1%. 1H NMR (DMSO-d6) 400 MHz δ: 11.55 (s, 1H), 7.53 (dt, 2H, J=8.8 2.0 Hz), 7.34 (dt, 3H, J=8.0 2.0 Hz), 7.15 (dd, 1H, J=7.6 1.0 Hz), 6.86 (m, 2H), 4.53 (d, 1H, J=8.0 Hz), 4.37 (d, 1H, J=8.0 Hz), 4.10 (t, 2H, J=1.6 Hz), 2.90 (t, 2H, J=2.0 Hz), 2.12 (t, 2H, J=1.8 Hz).
Reaction SMILES: [Br-].[F:2][C:3]1[C:4]2[CH2:5][CH:6]3[C:15](=[N+:16]4CCCC4)[CH:9]([CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH2:8][CH2:7]3.Cl.NO.O.O.O.C([O-])(=[O:29])C.[Na+].C(O)C.O>O>[F:2][C:3]1[C:4]2[CH2:5][CH:6]3[C:15](=[N:16][OH:29])[CH:9]([CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH2:8][CH2:7]3
Reactant: CC(=O)[O-]
Reactant: Fc1cccc2c1CC1CCC(C2)C1=[N+]1CCCC1
Agent: Cl
Agent: NO
Agent: [Br-]
Solvent: CCO
Solvent: O
Product: ON=C1C2CCC1Cc1c(F)cccc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Step 2 (1.02 g, 3.02 mmol), hydroxylamine hydrochloride (624 mg, 9.05 mmol) and sodium acetate trihydrate (1.23 g, 9.05 mmol) in 2:1 ethanol-water (12 ml) were heated to reflux and allowed to cool to room temperature, then stirred for 18 hours at this temperature. Water (10 ml) was added and the mixture filtered. The white solid was washed with water and dried under vacuum. 590 mg (89%). m/z 220 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CC(C)=O>[CH3:24][S:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1)(=[O:27])=[O:26]
Reactant: Nc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reaction time: 20 h

Procedure:
To a solution of 2-(p-aminophenyl)-4-trifluoromethylimidazole (3.0 g.) in acetone (50 ml.) and triethylamine (2.7 g.) is added methanesulfonyl chloride (1.5 g.). After refluxing for four hours, a second portion of methanesulfonyl chloride (1.5 g.) is added. Reflux is continued 20 hours, a third portion of methanesulfonyl chloride (1.5 g.) is added and reflux continued another four hours. The reaction mixture is filtered and concentrated to an oil which, upon trituration with water, affords a solid. After chromatography on silica gel and recrystallization from a mixture of acetonitrile and water 1.3 g. of 2-(p-methylsulfonamidophenyl)-4-trifluoromethylimidazole, m.p. 253°-255° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=O)[N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[NH3:30]>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([NH2:30])=[O:27])[N:24]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)n1
Reactant: N
Solvent: CCO
Product: NC(=O)c1csc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)n1
Temperature: 39 °C
Reaction time: 24 h

Procedure:
In a flask was placed ethyl 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)thiazole-4-carboxylate (83.6 mg, 0.2 mmol) and EtOH (3 mL) was added. Then, NH3(aq) (24 mL) was added and the resulting mixture was heated to 38-40° C. for 24 h. The reaction did not go completion and another portion of NH3(aq) (24 mL) was added. The resulting mixture was stirred continuously at 38-40° C. for another 24 h. The resulting mixture was then concentrated to remove most of the solvent. The resulting white solid was filtered and washed with H2O (3 mL), 20% CH2Cl2/hexane (5 mL×2), then dried to yield as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[OH:22]O>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:22])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: OO
Reactant: N#Cc1cc(Sc2ccccc2)[nH]c1-c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(S(=O)c2ccccc2)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.9 %

Procedure:
A mixture of 2-(p-chlorophenyl)-5-(phenylthio)pyrrole-3-carbonitrile (916 mg, 2.95 mmol) and 30% hydrogen peroxide solution (105.3 mg, 3.09 mmol) in acetic acid is stirred at room temperature for 3 days, diluted with water and filtered to obtain a solid. The solid is recrystallized from methanol to give the title product as a grey solid (510 mg, mp 169°-170° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[C:14]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1nn(-c2ccccc2)c2ccccc12
Temperature: 30 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a mixture of methyl 1H-indazole-3-carboxylate (3.44 g), phenylboronic acid (4.76 g), pyridine (2.84 mL) and N,N-dimethylformamide (70 mL) was added copper (II) acetate (5.32 g), and the mixture was stirred at 30° C. overnight. The insoluble material was filtered off, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (1.58 g, 32%) as a pale-yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH2:4][OH:5].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(O)C>[C:13]([NH:17][C:18]([NH:2][C@H:3]([CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH2:4][OH:5])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)CCc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)CCc1ccsc1
Temperature: 20 °C

Procedure:
A solution of 1.2 g of (2R)-2-amino-4-(3-thienyl)-1-butanol, hydrochloride in 40 mL of ethanol, is combined with 1.1 mL of tert-butylisothiocyanate and 1 mL of triethylamine and magnetically stirred under inert atmosphere at a temperature of about 20° C., then heated for 20 hours at a temperature of about 50° C. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature of about 50° C. The solution is evaporated to obtain a residue, which is purified by chromatography under argon pressure (70 kPa), on a column of silica gel (particle size 60-200 μm; diameter 3.6 cm; height 20 cm), eluting with a mixture of cyclohexane-ethylacetate (60/40 by volume) and obtaining fractions of 30 mL. The fractions containing the expected product are collected and evaporated under reduced pressure (2 kPa) at a temperature of about 40° C. About 0.73 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(2-thien-3-ylethyl)ethyl]thiourea are obtained in the form of a colorless oil. [1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 1.42 (s, 9H); from 1.60 to 1.95 (mt, 2H); 2.60 (t large, J=8 Hz, 2H); 3.38 (mt, 1H); 3.50 (mt, 1H); 4.26 (mf, 1H); 4.80 (mf, 1H); 7.01 (dd, J=5 and 1.5 Hz, 1H); from 7.15 to 7.25 (mt, 2H); 7.20 (s, 1H); 7.46 (dd, J=5 and 3 Hz, 1H)].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>O1CCOCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:21][NH2:22])[C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1c(OCc2ccccc2)ccnc1Cl
Reactant: NN
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NNc1nccc(OCc2ccccc2)c1C(F)(F)F
Temperature: 160 °C
Yield: 82.9 %

Procedure:
To a suspension of compound D7 (1.09 g g, 3.789 mmol) in 1,4-dioxane (9 ml), was added hydrazine monohydrate (3.676 ml, 75.78 mmol). The reaction mixture was heated at 160° C. under microwave irradiation for 30 min. After cooling the resulting solution was concentrated in vacuo. The residue thus obtained was dissolved in DCM and washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to yield intermediate compound D8 (0.890 g, 83%) as a white solid.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:8]=[CH:7][C:6](C)=[C:5]([C:10]#[CH:11])[CH:4]=1.[OH-].[K+].[CH3:16]O>O>[C:8]1([CH3:16])[CH:3]=[CH:4][C:5]([C:10]#[CH:11])=[CH:6][CH:7]=1
Reactant: CO
Reactant: C#Cc1cc([Si](C)(C)C)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C#Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
34.7 g (0.184 mol) of 4-trimethylsilyl ethynyl toluene was dissolved in 500 ml of methanol in a 1 L round-bottomed flask equipped with a stirrer. 10 ml of 20% KOH in water was added to the resulting solution. The reaction mixture was then stirred at room temperature for 5 hours. After the reaction was completed, water were poured into the flask. The reaction mixture was then extracted with ethyl ether several times. The combined extract was washed with water several times, and then dried with anhydrous magnesium sulfate. The solvent was removed, to give 21 g (98% yield) of yellow liquid.
Reaction SMILES: [PH2](O)=O.[CH2:4]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](N)=[N:17][N:18]2[CH2:21][C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N(OCC(C)C)=O>CO.O>[CH2:4]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH2:21][C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@@H](O)Cn1nc(N)c2ccc(OCc3ccccc3)cc21
Agent: CC(C)CON=O
Agent: O=[PH2]O
Solvent: CO
Solvent: O
Product: C[C@@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Reaction time: 3 h

Procedure:
Hypophosphorous acid (3.45 L of a 50% (w/w) aqueous solution) was added to a stirred solution of 2 (1975 g, 6.65 mol) in 23.7 L of methanol under a nitrogen atmosphere. Isobutyl nitrite (1576 mL, 13.3 mol) was added in two portions, keeping the reaction temperature below 53° C. After 3 hours, a solution of Na2HPO4 (8.5 kg) in 70 L of water was added, and the mixture was extracted with ethyl acetate (30 L then 15 L). The combined organic extracts were washed with brine, dried (Na2SO4), treated with decolorizing charcoal, filtered and concentrated in vacuo. The product was purified by trituration with ethyl acetate-hexane followed by elution through silica using an acetone-hexane gradient, to give after concentration in vacuo, 1260 g (67%) of 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.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.[NH2:50][C@H:51]1[C@@H:55]([OH:56])[CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]1>CN(C=O)C>[C:60]([O:59][C:57]([N:53]1[CH2:54][C@H:55]([OH:56])[C@H:51]([NH:50][C:12]([C:11]2[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:16][CH:15]=2)=[O:14])[CH2:52]1)=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)c2ccc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of 6-(3-fluorophenyl)nicotinic acid (391 mg, 1.8 mmol ) in DMF (10 mL) at 0° C. was added HATU (753 mg, 1.98 mmol) and DIPEA (0.47 mL, 2.07 mmol ). After 15 min, cis-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate was added and the reaction stirred at room temperature for 5 hrs. The solvent was removed in vacuo and the residue diluted with ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried (MgSO4) and the solvent removed to give an oil, which after chromatography (silica, 65% ethyl acetate:hex) to give the desired product, cis-tert-butyl-3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate (420 mg, 58%). LC/MS (M+H)=401.9 observed, 402.18 expected.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:31])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2].[F:33][C:34]([F:48])([F:47])[C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:46])[CH2:42][C:43](=O)[CH3:44])=[CH:37][CH:36]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:31]/[C:43](/[CH3:44])=[CH:42]\[C:41](=[O:46])[C:38]1[CH:39]=[CH:40][C:35]([C:34]([F:33])([F:47])[F:48])=[CH:36][CH:37]=1)[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)N/C(C)=C\C(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 105 a], [rac]-2-amino-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester was reacted with 1-(4-trifluoromethyl-phenyl)-butane-1,3-dione in toluene in the presence of a catalytic amount of p-toluene sulfonic acid at reflux to yield [rac]-2-[1-methyl-3-oxo-3-(4-trifluoromethyl-phenyl)-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 105 b] to yield [rac]-2-[1-methyl-3-oxo-3-(4-trifluoromethyl-phenyl)-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=O.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1c(F)cc(Cl)cc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(F)cc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dichloro-6-fluorobenzamide (5.07 mmol) (US 20060178386) in 74 mL DCM were added Et3N (15.2 mmol) followed by TFAA (10.1 mmol) at 0° C. After 30 min, water was added, the organic layer was separated and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc ( 4/1 to ⅓) gives the desired compound as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH:40]=[C:41]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:30])=[C:9]([N+:27]([O-:29])=[O:28])[CH:10]=2)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)Nc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Yield: 51.8 %

Procedure:
Prepared from (2-nitro-4-tributylstannanyl-phenyl)-carbamic acid tert.-butyl ester (Example D2) (3.18 g, 6.06 mmol) and 4-trifluoromethylsulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert.-butyl ester (1.99 g, 6.0 mmol) [prepared from Boc-4-piperidone by treatment with LDA in THF at −78° C. followed by reaction with N-phenyl-bis(trifluoromethanesulfonimide) according to Wustrow et al. Synthesis 1991, 1993] according to the general procedure E. Obtained as an orange solid (1.304 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[CH:21]([OH:24])([CH3:23])[CH3:22].O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:24][CH:21]([CH3:23])[CH3:22])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)O
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.1 %

Procedure:
To a stirred solution of 4-chloro-3-nitrobenzoyl chloride (20.5 g) in ethyl acetate (80 cm3) was added a solution of triethylamine (10.1 g) and i-propylalcohol (6 g) in ethylacetate (40 cm3) over 15 mins causing a slight exotherm. The reaction was stirred at the ambient temperature for a further 3.5 hours and then poured into water. The layers were separated and the aqueous layer was extracted with ethyl acetate and the combined ethyl acetate layers were washed with 10% HCl, brine and dried with sodium sulphate. Filtration and evaporation gave iso-propyl 4-chloro-3-nitrobenzoate as a yellow solid (22.5 g). 1H nmr (CDCl3) d: 8.49 (1H, d), 8.17 (1H, dd), 7.64 (1H, d), 5.29 (1H, septet), 1.40 (6H, d). Mpt 61°-62° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH:15]([CH2:18][CH3:19])[CH2:16][OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH:15]([CH2:18][CH3:19])[CH2:16][O:17][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COC(=O)CBr
Reactant: CCC(CO)n1cnc2c(N)nc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(COCC(=O)OC)n1cnc2c(N)nc3ccccc3c21
Reaction time: 0.25 h

Procedure:
2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (25 mg, 0.0975 mmol) was placed in a 2 dram (7.4 mL) vial. Sodium hydride (5 mg of a 60% dispersion in mineral oil, 0.117 mmol) and N,N-dimethylformamide (1 mL) were added. The vial was placed on a sonicator for 15 minutes at ambient temperature to allow the alkoxide to form. Methyl bromoacetate (11 μL, 0.117 mmol) was added. The reaction was sonicated at ambient temperature for 1.5 hours. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The reaction mixture was purified by semi-preparative HPLC using Method A Mass Measurement (Da.): Theoretical mass=328.1535, Measured mass=328.1534.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:16][C:17]1[N:22]=[C:21]2[NH:23][CH:24]=[N:25][C:20]2=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[N:22]=[C:21]2[N:23]([CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[O:8])[CH:24]=[N:25][C:20]2=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCCC1Cl
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: O=C1CCCCC1n1cnc2ccc(OCc3ccccc3)nc21

Procedure:
From 2-chlorocyclohexanone and 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine, prepared in a similar manner as the one described in Example 1.1, Step C, the title compound was obtained. LCMS m/z=322.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[CH3:1][C:2]1[C:3]([O:16][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(Oc2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 1(a) above, by the reaction of 1.1 g (5 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthol with 0.89 g (4.1 mmol) of methyl 4-bromobenzoate, 670 mg (46%) of the expected methyl ester of melting point 133-5° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>>[CH3:1][O:2][C:3]([C:5]1([CH2:14][CH2:13][CH2:12][CH2:11][Cl:10])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCC1
Reactant: ClCCCCBr
Product: COC(=O)C1(CCCCCl)CCCC1
Yield: 64 %

Procedure:
1-(4-Chlorobutyl)cyclopentane carboxylic acid methyl ester was prepared from cyclopentane carboxylic acid methyl ester and 4-chloro-1-bromobutane using the procedure described in example 7 to give a 64% yield. HR MS (C11H19ClO2): Obs. mass, 218.1072. Calcd. mass, 218.1074, (M+).