Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[O:9]([C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-:23].[Na+]>>[O:9]([C:16]1[CH:21]=[CH:20][C:19]([O:23][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: CC(C)N1CC(O)C1
Reactant: OC1(Oc2ccccc2)C=CC=CC1
Agent: [Na+]
Product: CC(C)NCC(O)COc1ccc(Oc2ccccc2)cc1
Temperature: 160 °C
Yield: 58 %

Procedure:
To a mixture of 5.8 parts of 1-(iso-propyl)-3-azetidinol and 9.3 parts of 1-phenoxyphenol 0.1 part of sodium hydroxide was added, and the mixture was heated under nitrogen gas at 160° C. for 18 hours. The reaction mixture was cooled and extracted with ether. The extract was washed in water and then the solvent was distilled off. Recrystallization of the residue gave 16.1 parts of 1-(p-phenoxyphenoxy)-3-(iso-propylamino)-2-propanol having a melting point of 72°-74° C. The yield was 58%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([NH2:16])=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.B.C1COCC1.Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:14][NH2:16])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reaction time: 0.08 h

Procedure:
To a solution of 0.93 g (2.3 mmol) (+) or (−)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetamide in tetrahydrofuran were added 0.29 ml (2.3 mmol) boron trifluoride ethyl etherate. The mixture was stirred for 5 min. and then 4.61 ml (4.61 mmol) borane THF complex (1M solution in tetrahydrofuran) were added dropwise. The mixture was stirred at 50° C. for 55 h. The solution was poured onto 12 ml tetrahydrofuran and 5 ml methanol (gas evolution) and stirred for 1 h. Then 50 ml 1M aqueous hydrochloric acid were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with 10 ml 1M aqueous hydrochloric acid. The combined aqueous layers were adjusted to pH 10 using 32% aqueous sodium hydroxide and 1M aqueous sodium hydroxide solution. The turbid mixture was extracted three times with dichloromethane. The organic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness. White foam (22%). MS (Turbo Spray): m/z=390.3 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][CH3:8])(=[O:4])[CH2:2][CH3:3].[CH:10]([CH:12]=[CH2:13])=[O:11].CC1C=C(C)C=C(C)N=1>S(=O)(=O)(O)O>[C:1]([O:5][CH:6]([O:9][C:10](=[O:11])[CH2:12][CH3:13])[CH:7]=[CH2:8])(=[O:4])[CH2:2][CH3:3]
Reactant: C=CC=O
Reactant: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)O
Solvent: Cc1cc(C)nc(C)c1
Product: C=CC(OC(=O)CC)OC(=O)CC
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
To a solution of 345 g (2.65 mols) propionic anhydride and 1.05 g concentrated sulfuric acid maintained at 45°-50° C was added dropwise 140 g (2.5 mols) acrolein over a period of 15 minutes. The reaction mixture was stirred for an additional 10 minutes. A 2.6 g-sample of 2,4,6-trimethyl-pyridine was then added and the reaction mixture stirred at about 25° C. for about 17 hours. The reaction mixture was then distilled through a short column to give 268 g of the product as a slightly yellow liquid, b.p. 96°-101° C (0.25 mm Hg).
Reaction SMILES: C(OC(OC(C)(C)C)=O)(O[C:4](C)(C)[CH3:5])=O.[N+:16]([CH2:19][C@@H:20]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:38]=1)[CH2:21][C:22]([N:24]1[C@H:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][O:26][C:25]1=[O:36])=[O:23])([O-])=[O:17].C(Br)=C.C1COCC1>CN(C)C1C=CN=CC=1.CCOC(C)=O>[O:17]1[CH:5]=[CH:4][C:19]([C@@H:20]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:38]=2)[CH2:21][C:22]([N:24]2[C@H:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27][O:26][C:25]2=[O:36])=[O:23])=[N:16]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(C[C@@H](C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C=CBr
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(C[C@H](c1cccc(OCc2ccccc2)c1)c1ccon1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.6 %

Procedure:
At room temperature, di-t-butyl dicarbonate (0.502 g, 2.30 mmol) was added to a solution of (R)-4-benzyl-3-((R)-3-(3-(benzyloxy)phenyl)-4-nitrobutanoyl)oxazolidin-2-one (94.1B) (0.727 g, 1.53 mmol), vinyl bromide, (1.0 M solution in THF (16.9 mL, 16.9 mmol), N,N-dimethylpyridin-4-amine (DMAP) (0.0187 g, 0.153 mmol) and TEA (0.256 mL, 1.84 mmol). The mixture was stirred at room temperature for 24 hours. The reaction was then diluted with EtOAc (200 mL) and washed with sodium bicarbonate solution and brine. The organic phase was dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:2 EtOAc/hexane) and gave 558 mg of 94.1C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[C:11]([C:20]([OH:22])=O)[CH:10]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH:33][C:20]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:14]=[C:13]([N:15]3[CH:19]=[N:18][N:17]=[N:16]3)[CH:12]=2)=[O:22])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccccc1-c1cc(C(=O)O)cc(-n2cnnn2)c1
Reactant: COc1cccc(CCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)c2cc(-c3ccccc3OC)cc(-n3cnnn3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2′-Methoxy-5-tetrazol-1-yl-biphenyl-3-carboxylic acid 0.9 g, 3 mmol), 2-(3-methoxy-phenyl)-ethylamine (0.5 mL), EDCI (0.6 g), HOBt (0.4 g) were added to methylene chloride (9 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between 1N aqueous HCl and EtOAc, and the combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3-20%, 5% NH4OH in MeOH/methylene chloride) to give 1.5 g of 2′-methoxy-5-tetrazol-1-yl-biphenyl-3-carboxylic acid[2-(3-methoxy-phenyl)-ethyl]-amide as a white solid, MS (M+H)=430.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[N+](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:1]([O:3][CH:4]1[CH2:5][CH:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: C=COCC
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A solution of ethyl vinyl ether (4.5 mL, 47 mmol, 4.9 equiv.) and rhodium(II) acetate dimer (20.0 mg, 45.2 μmol, 4.8 mol %) in DCM (20 mL) at ambient temperature was treated with ethyl 2-diazoacetate (1.00 mL, 9.51 mmol) in 0.1 mL portions over 10 mins, allowing effervescence to subside between additions. The resulting green solution was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was dissolved in diethyl ether and washed with water, and with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford crude ethyl 2-ethoxycyclopropanecarboxylate as a golden yellow oil (1.36 g, 90%) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[CH2:10]=O.[SH:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19]>C(O)(=O)C.Cl.O.C(=O)([O-])[O-].[K+].[K+]>[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]([CH2:10][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:7][CH:8]=1)[CH3:9]
Reactant: CNC(=C[N+](=O)[O-])NCCS
Reactant: CN(C)Cc1ccco1
Reactant: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 120 h

Procedure:
N,N-Dimethyl-2-furanmethanamine (125 mg) was dissolved in glacial acetic acid (1 ml) and paraformaldehyde (30 mg) added. A solution of N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine (354 mg) in concentrated hydrochloric acid (1 ml) and glacial acetic acid (1 ml) was added dropwise and the mixture left to stand at room temperature for 5 days. The solution was diluted with water (30 ml), saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts were purified by preparative layer chromatography to give the title compound as Example 15 (89 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5]O.S([O-])([O-])(=O)=O.[Ca+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:43]Br>O.CCCCCC.CN(C)C=O>[Br:43][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCCC(C)CCCC(C)CCCO
Reactant: BrBr
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCCBr

Procedure:
Into a 250 ml, three-necked, round-bottom flask equipped with a thermometer, serum cap, argon blubber and a magnetic stir bar was added 10 g (40 mmol) of 4,8,12-trimethyltridecanol, 30 ml of purified dimethylformamide (DMF) (stored over calcium sulfate prior to distillation) and 11.2 g (43 mmol) of triphenylphosphine. The solution was cooled to 0° C. before 2.19 ml (43 mmol) of bromine was added via syringe at such a rate that the temperature remained below 30° C. At the end of the addition a persistent orange color remained. The reaction was poured into 200 ml of hexane and 200 ml of water. The aqueous layer was extracted 3×200 ml of hexane. The combined organic layers were rinsed with 300 ml of saturated sodium bicarbonate, 100 ml brine, and were dried with 80 cc of sodium sulfate. The solvent was removed at reduced pressure with a rotary evaporator to afford a mixture of oil and solid. The mixture was triturated with hexane and filtered over a short plug of 40 g of silica gel eluting with hexane. Removal of the solvent left 10.7 g of colorless oil. Distillation through a 10 cm, vacuum jacqueted vigreaux afforded 9.7 g of colorless product, i.e. 1-bromo-4,8,12-trimethyltridecane, bp 119°-20° C. at 0.15 mm Hg.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:5]=1.Cl.N1CCC(C(C2C=CC3C(=CC=C(Cl)C=3)C=2)=O)CC1.Br[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)=[O:50].ClCCCC(C1C=CC(F)=CC=1)=O>>[F:22][C:3]([F:2])([F:21])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)=[O:50])[CH2:17][CH2:16]2)[CH:5]=1
Reactant: FC(F)(F)c1cc(CC2CCNCC2)cc2ccccc12
Reactant: COc1ccc(C(=O)CCCCCBr)cc1
Agent: Cl
Agent: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Product: COc1ccc(C(=O)CCCCCN2CCC(Cc3cc(C(F)(F)F)c4ccccc4c3)CC2)cc1

Procedure:
When in the procedure of Example 25, 4-[(4-trifluoromethyl-2-naphthyl)methyl]piperidine hydrochloride is substituted for 6-chloro-2-naphthyl 4-piperidyl ketone hydrochloride and 6-bromo-1-(4-methoxyphenyl)-1-hexanone substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, 6-[4-((4-trifluoromethyl-2-naphthyl)methyl)-1-piperidyl]-1-(4-methoxyphenyl)-1-hexanone is obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[CH2:10][CH2:11][CH2:12][C:6]=12
Reactant: O=[N+]([O-])c1cnc2c(c1O)CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A solution of 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-ol (1.424 g, 7.904 mmol) in phosphoryl chloride (11.0 mL, 118 mmol) was heated at 110° C. in a sealed flask under nitrogen for 2 h. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 50% aq. NaOH to pH 7. The resulting mixture was extracted three times with EtOAc, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a brown solid (0.82 g, 52%). LCMS calc. for C8H8N2O2(M+H)+: m/z=199.3. Found: 199.2.
Reaction SMILES: C1(C(=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([B:46]2[O:50][C:49]([CH3:52])([CH3:51])[C:48]([CH3:54])([CH3:53])[O:47]2)=[C:42]([F:55])[CH:41]=1>C1COCC1.O.Cl>[NH2:14][CH:15]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([B:46]2[O:50][C:49]([CH3:52])([CH3:51])[C:48]([CH3:54])([CH3:53])[O:47]2)=[C:42]([F:55])[CH:41]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC1(C)OB(c2ccc(CBr)cc2F)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(N)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a stirred solution of ethyl 2-((diphenylmethylene)amino)acetate (300 mg, 1.12 mmol) in anhydrous THF (3 mL) at −78° C. was added 0.5 M KHMDS in toluene (2.46 mL, 1.23 mmol). After stirring for 15 min, 2-(4-(bromomethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (353 mg, 1.12 mmol) was added. The reaction mixture was stirred at −78° C. for 3 h and warmed to −20° C. To the mixture was added 6 N Hydrochloric acid (0.5 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (5 mL) and 1 N HCl (5 mL) and then extracted with diethyl ether. The aqueous layer was basified with 1N NaOH and then extracted with EtOAc (3×10 mL). The combined organic extract was washed with water, brine and then dried over MgSO4. Filtration and concentration gave 177 mg (46%) of ethyl 2-amino-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate which was used in the next step without purification. LCMS-ESI (m/z) calculated for C17H25BFNO4: 337.2. found 338.2 [M+H]+, tR=2.78 min (Method 1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[O:28]1[CH2:31][C:30](=O)[CH2:29]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:28]1[CH2:31][CH:30]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:16]([NH:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][NH:23]4)[CH3:17])[CH2:3][CH2:2]2)[CH2:29]1
Reactant: O=C1COC1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C2COC2)CC1
Reaction time: 4 h

Procedure:
To a mixture of (S)—N-(1-(1-(piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-purin-6-amine from Example 113 (99 mg, 0.273 mmol) in anhydrous DCE (10 mL) was added oxetan-3-one (32 μL, 0.546 mmol) followed by AcOH (16 μL, 0.273 mmol) and 4 Å (angstrom) powdered molecular sieves (0.1 g). After stirring for 4 h, sodium triacetoxyborohydride (116 mg, 0.546 mmol) was added and stirring was continued for 48 h. The crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with diethyl ether and MeOH affording 129 as a white solid (50 mg, 44%). LCMS: RT 1.61 min [M+H]+ 419.1. 1H NMR (DMSO, 400 MHz, 80° C.): δ 8.25 (1H, s), 8.05 (1H, s), 7.65-7.59 (2H, m), 7.44 (1H, bs), 7.20-7.13 (2H, m), 6.16-6.04 (1H, m), 4.63-4.39 (6H, m), 3.50-3.42 (1H, m), 2.93-2.85 (1H, bd, J=10.45 Hz), 2.76-2.69 (1H, bd, J=10.45 Hz), 2.40-2.28 (1H, m), 2.04-1.93 (1H, t, J=11.60 Hz), 1.90-1.81 (1H, m), 1.76-1.53 (6H, m)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[F:25].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2([C:39](O)=[O:40])[CH2:38][CH2:37]2)=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([S:15][CH3:16])[CH:7]=[C:6]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:39]([C:36]2([C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[O:35])[CH2:38][CH2:37]2)=[O:40])=[CH:20][C:19]=1[F:25]
Reactant: COc1cc2nc(SC)cc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a mixture of 4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine (0.22 g, 0.61 mmol) and 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.16 g, 0.73 mmol) in DMF (5 mL) was added TEA (0.25 mL, 1.8 mmol) followed by HATU (0.57 g, 1.5 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water and extracted with DCM (2×). The combined extracts were washed with 5% LiCl(aq.) (3×), water, (1×) and brine (1×), followed by drying over Na2SO4 and concentration in vacuo. The crude solids were purified by preparatory HPLC with ammonium acetate, affording N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.39 g, 11% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 9.94 (s, 1H), 7.83 (d, 1H), 7.59 (m, 2H), 7.56 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1H), 7.09 (t, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H), 1.40 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=O)[CH2:7][CH2:6]2.Cl.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.O>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8]1[NH:22][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:7]=1[CH2:6]2
Reactant: COc1c(C)cc2c(c1C)CCC2=O
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 5-methoxy-4,6-dimethyl-1-indanone (3.0 g, 16 mmol) and phenylhydrazine hydrochloride (2.3 g, 16 mmol) was heated to reflux in ethanol (20 cm3) containing concentrated hydrochloric acid (2 cm3). The reaction mixture was heated at reflux for 6 hours, and cooled to room temperature. Water was added, and the resulting precipitate filtered off. This product was dried in a vacuum oven, and purified by column chromatography to yield the title compound as a colourless solid. Yield: 2.8 g, (67%). M.p. 177° C. from ethyl acetate petrol (60°-80° C.). 1H NMR (CDCl3)δ: 2.36 (6H, s,), 3.56 (2H, s,), 3.76 (3H, s,), 7.1-7.6 (5H, m,), 8.2 (1H,br,).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1ccccc1F
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1ccccc1F

Procedure:
Prepared by Procedure U and Scheme AK using 2-fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)C.O>[C:27]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2ncccc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)N1CC=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Quinoline (19.37 g, 150 mmol) was dissolved in anhydrous diethyl ether (500 ml) and cooled to 0° C. under inert atmosphere. DIBAL, 1.5 M in toluene (100 ml, 150 mmol) was added dropwise over 2 hrs and the reaction mixture was stirred at 0° C. for 30 min. Acetic anhydride (500 ml) was added dropwise over 30 min and the reaction mixture was stirred at 0° C. for 30 min. H2O was added cautiously. The reaction mixture was extracted with diethyl ether and concentrated to give N-acetyl-1,2-dihydroquinoline (11.5 g, 44%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[O:16][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[N:17]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2nc(-c3ccccn3)co2)c1
Yield: 24.7 %

Procedure:
Using the procedures of Kelly et al., J. Org. Chem., (1996) 61:4623-4633, a solution of 2-bromoacetylpyridine (120 mg, 0.6 mmol) in toluene (5 mL) was treated with 3-chlorobenzamide (300 mg, 1.9 mmol) and the mixture heated in a sealed vial at reflux for 60 hours. The mixture was then cooled and the solvent was removed in vacuo. Silica gel chromatography using a gradient of hexane to ethyl acetate afforded 38 mg (9%) of 2-[3-chlorophenyl]-4-[pyridin-2-yl]-1,3-oxazole as a pale yellow solid. 1H-NMR (CDCl3), δ (ppm): 8.62 (d, 1H), 8.35 (s, 1H), 8.15 (m, 1H), 8.00 (m, 2H), 7.80 (td, 1H), 7.42 (m, 2H), 7.23 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8]S[C:5]=2[CH2:4][CH2:3]1.[O:12]1C2CCCC(=O)C=2C=C1>>[CH3:1][CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][O:12][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1CCc2sccc2C1=O
Reactant: O=C1CCCc2occc21
Product: CC1CCc2occc2C1=O

Procedure:
Following the procedure for the preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting 6,7-dihydro-1-benzofuran-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.24, 1.95, 2.25, 2.55, 2.93, 6.68, 7.33; MS (EI) m/z (rel. intensity) 150 (M+, 54), 150 (54), 121 (10), 109 (8), 108 (99), 86 (26), 84 (39), 80 (56), 52 (19), 51 (26), 50 (7). HRMS (FAB) calcd for C9H10O2+H 151.0759, found 151.0760. Anal. Calcd for C9H10O2: C, 71.98; H, 6.71. Found: C, 71.55; H, 6.74; N, 0.19.