Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@@H:29]([O:33]C(=O)C5C=CC([N+]([O-])=O)=CC=5)[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@@H:29]([OH:33])[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33.2 %

Procedure:
A solution of tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.020 g, 0.032 mmol) in THF:H2O (2:1, 0.3 mL) was cooled to about 0° C. and treated with LiOH—H2O (0.0027 g, 0.065 mmol). The reaction was stirred at about 0° C. for about 5 minutes, followed by about room temperature for 1.5 hours. The reaction was concentrated and diluted with saturated NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was purified by preparative HPLC to yield tert-butyl 5-chloro-1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.005 g, 36%). LCMS (APCI+) m/z 471, 473 [M+H]+; Rt=4.11 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:15]([CH3:21])=[N:14]1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[N:17]([CH3:25])[C:16](=[O:20])[C:15]([CH3:21])=[N:14]1
Reactant: CI
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)n(C)c1=O
Yield: 64.9 %

Procedure:
In a manner similar to Example III, Step G, the reaction of 0.28 g (0.00085 mole) of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione with 0.037 g (0.00093 mole) of sodium hydride (60% in oil) and 0.13 g (0.00093 mole) of iodomethane in 10 mL of N,N-dimethylformamide produced 0.19 g of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-4,6-dimethyl-1,2,4-triazine-3,5(2H,4H)-dione as a low melting solid, Compound 13 in the tables.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br/[CH:19]=[CH:20]/[CH3:21].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])(/[CH:19]=[CH:20]/[CH3:21])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: C/C=C/Br
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C/C=C/C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (636 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from trans-1-bromo-1-propene (1.35 mL), a small iodine flake, and magnesium powder (382 mg) in THF (5 mL). The resulting mixture was then stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a yellow solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.[O:12]1[C:16]2[C:17](=[O:21])[CH2:18][CH2:19][CH2:20][C:15]=2[CH:14]=[CH:13]1.[Cl-].[NH4+]>CCCCCC.CCOCC.C1COCC1>[O:9]1[CH:10]=[CH:11][C:7]([C:17]2([OH:21])[C:16]3[O:12][CH:13]=[CH:14][C:15]=3[CH2:20][CH2:19][CH2:18]2)=[CH:8]1
Reactant: Brc1ccoc1
Reactant: O=C1CCCc2ccoc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccoc2)CCCc2ccoc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a solution of 10.2 ml (0.102 mol) of 10M n-butyllithium in hexane in 200 ml of ether cooled to -78° C. was added dropwise 15 g (0.102 mol) of 3-bromofuran and the mixture was stirred for 15 min. To the above cooled mixture was added 12.61 g (0.092 mol) of 4,5,6,7-tetrahydrobenzofuran-7-one in 50 ml of THF and the mixture was allowed to warm to room temperature, and then stirred for 15 min. To the mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 ml), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 16.3 g (86%) of 4,5,6,7-tetrahydro-7-(3-furyl)-benzofuran-7-ol, a red oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH:17][C:18](=O)[C:19]([F:22])([F:21])[CH3:20])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:45]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:17]=[C:18]([Cl:45])[C:19]([F:22])([F:21])[CH3:20])[CH:5]=1
Reactant: COC(=O)c1cc(NC(=O)C(C)(F)F)cc(-c2ccc(C)cn2)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc(N=C(Cl)C(C)(F)F)cc(-c2ccc(C)cn2)c1
Temperature: 95 °C
Reaction time: 48 h

Procedure:
3-(2,2-Difluoro-propionylamino)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (0.630 g, 1.88 mmol) and triphenyl phosphine (0.989 g, 3.77 mmol) were added to 15 mL of CCl4. The reaction mixture was heated to 95° C. and stirred under nitrogen for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 0.612 g of 3-(1-chloro-2,2-difluoro-propylideneamino)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[C:24]([F:38])[CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30](=[CH:19][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:7](=[O:18])[C:6]=4[C:2]=2[CH3:1])[C:31](=[O:37])[NH:32]3)=[C:24]([F:38])[CH:23]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4F)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 51.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(4-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(4-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 51.6%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=2)[C:28]([O:30]CC2C=CC=CC=2)=[O:29])O1.C(=O)([O-])[O-].[Na+].[Na+].O>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.CN(C)C=O>[C:10]([O:9][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:25]2[CH:40]=[CH:39][CH:38]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=2)=[CH:3][CH:4]=1)=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc(C(=O)OCc3ccccc3)c2)OC1(C)C
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(C(=O)O)c2)cc1
Temperature: 80 °C
Reaction time: 1.17 h
Yield: 79.8 %

Procedure:
To a mixture of tert-butyl N-(4-bromobenzyl)carbamate (0.425 g), benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane-2-yl)benzoate (0.553 g), sodium carbonate (0.315 g), water (1.3 mL) and N,N-dimethylformamide (6.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.086 g), and the resulting mixture was stirred at 80° C. for 70 minutes. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and water (15 mL). The organic layer was washed successively with water/brine (2/1, 15 mL×2) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the residue (1.0 g) in ethanol (7.4 mL) was added 1 mol/L aqueous sodium hydroxide (2.23 mL), and the resulting mixture was stirred at 80° C. for 80 minutes. One mol/L aqueous sodium hydroxide (2.23 mL) was added and stirring was continued for additional 2 hours. The reaction mixture was cooled to room temperature. One mol/L hydrochloric acid (4.46 mL) was added and then the whole was partitioned between ethyl acetate (35 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2-1/2) to give 4′-(tert-butoxycarbonylaminomethyl)biphenyl-3-carboxylic acid (0.388 g). To a solution of the carboxylic acid (0.330 g) in N,N-dimethylformamide (5.0 mL) were added successively dimethylamine hydrochloride (0.123 g), diphenylphosphoryl azide (0.435 mL) and triethylamine (0.422 mL), and the resulting mixture was stirred at room temperature for 67.5 hours. One mol/L hydrochloric acid (10 mL) was added and the whole was extracted with ethyl acetate (30 mL). The organic layer was washed successively with water (10 mL), saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=8/1) to give the title compound (0.246 g).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][C:16]1=[O:21])([CH3:14])[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[BrH:26]>C(Cl)(Cl)Cl>[Br:26][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C:16](=[O:21])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22]([O:24][CH3:25])=[O:23])[CH2:4][C@@H:3]1[OH:1]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Br
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-Epoxy-17β-methoxycarbonyl-5α-androstan-11-one (500 mg.) in chloroform (32 ml.) was stirred with 48% aqueous hydrogen bromide (10 ml.). After an hour the mixture was washed with an excess of aqueous sodium bicarbonate and with water, was dried (MgSO4) and evaporated to a froth (628 mg.) Crystallisation from ethyl acetate/light petroleum afforded title compound (330 mg.) as colourless needles; m.p. 205°-208°; [α]D + 76°,
Reaction SMILES: [NH2:1][C:2]1([CH2:20][O:21][CH2:22][CH2:23][C:24]#[N:25])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.C[Al](C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:19][C:5]1[CH:4]=[C:3]2[C:8]([O:9][C:10]3[C:11]([F:18])=[CH:12][C:13]([O:16][CH3:17])=[CH:14][C:15]=3[C:2]32[CH2:20][O:21][CH2:22][CH2:23][C:24]([NH2:25])=[N:1]3)=[CH:7][CH:6]=1
Reactant: COc1cc(F)c2c(c1)C(N)(COCCC#N)c1cc(Br)ccc1O2
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(F)c2c(c1)C1(COCCC(N)=N1)c1cc(Br)ccc1O2
Temperature: 90 °C
Reaction time: 0.02 h

Procedure:
A 250-mL round-bottom flask was charged with 3-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)propanenitrile (2.78 g, 6.83 mmol) and toluene (45.5 mL) to give a pale-green solution. Trimethylaluminum (7.17 mL of a 2M solution in toluene, 14.34 mmol) was added, and a reflux condenser was attached. After stirring for 1 min, the flask was heated to 90° C. for 1 h. After this time, the mixture was cooled to RT. Sodium sulfate decahydrate (3.4 g) was added slowly over 5 min, and the mixture was stirred overnight. In the morning, the mixture was diluted with EtOAc (50 mL) and filtered through celite. The filter pad was washed with EtOAc (3×50 mL). The combined filtrates were concentrated to give a pale-yellow solid. The crude product was purified by chromatography on silica gel (0-10% MeOH/DCM) to give (E)-7′-bromo-4′-fluoro-2′-methoxy-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.53 (d, J=2.4 Hz, 1 H), 7.47 (dd, J=2.5, 8.6 Hz, 1 H), 7.18 (d, J=8.6 Hz, 1 H), 6.95 (dd, J=2.9, 12.3 Hz, 1 H), 6.69 (dd, J=1.5, 2.9 Hz, 1 H), 6.15 (br. s., 2 H), 3.83-3.69 (m, 5 H), 3.64-3.45 (m, 2 H), 3.00-2.74 (m, 2 H). MS m/z=411.0. Calc'd for C18H17BrFN2O3: 407.1.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:7][C:4]3[S:3][C:2]([Cl:1])=[CH:6][CH:5]=3)=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCc3ccc(Cl)s3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 40 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-chloro-5-(chloromethyl)thiophene in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 40% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.9 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.30-7.18 (m, 5H), 7.15 (d, J=3.8 Hz, 1H), 7.05 (d, J=3.8 Hz, 1H), 6.34 (dd, J=8.1, 2.7 Hz, 1H), 6.28 (d, J=2.7 Hz, 1H), 5.30 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 471.9 (M+1), 473.8 (M+3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]([C:22]([O:24]CC)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1.[ClH:27]>>[ClH:27].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:22]([OH:24])=[O:23])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CC(c2ccc(OC)cc2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Product: COc1ccc(C2CNCC(C(=O)O)C2)cc1

Procedure:
1.13 g (3.11 mmol) of 1-tert-butyl 3-ethyl 5-(4-methoxyphenyl)piperidine-1,3-dicarboxylate were added to 40 ml of aqueous 1 N hydrochloric acid solution, and the mixture was concentrated on a rotary evaporator. Yield: 829 mg (98% of theory)
Reaction SMILES: C([NH:8][C:9]([NH:11][C:12]1([CH2:33][O:34][SiH3:35])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:13]1[F:32])=[O:10])C1C=CC=CC=1>CC(O)=O.[Pd]>[C:28]([CH:14]1[C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([CH2:33][O:34][SiH3:35])([NH:11][C:9](=[O:10])[NH2:8])[CH:13]1[F:32])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)C1C(F)C(CO[SiH3])(NC(=O)NCc2ccccc2)C1(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)C1C(F)C(CO[SiH3])(NC(N)=O)C1(c1ccccc1)c1ccccc1
Reaction time: 96 h

Procedure:
In the Parr Hydrogenator flask with 1 mL AcOH and 10% Pd/C 0.15 g inside, 1-benzyl-3-(3-tert-butyl-diphenyl-siloxymethyl-2-fluoro-cyclobutyl)-urea in 5 mL AcOH was added. This was hydrogenolysed at 50 psi for 4 d, after which the crude mixture was filtered through celite and was purified by silica gel flash chromatography (CH2Cl2: MeOH=40:1) to give 0.15 g (63.3%, Rf=0.44 (CH2Cl2: MeOH=20:1) the desired product. IR (neat) νmax 3425, 3339, 2931, 2858, 1656, 1608, 1560, 1111, 701.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][C:15]([OH:17])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.ClC1C=CC=CC=1[NH2:27]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]([NH2:27])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1
Reactant: Nc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC(=O)CCC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Yield: 92 %

Procedure:
A solution of 3-phenyl-3-cyclohexanepropanoic acid (0.5 g, 2.15 mmol) and oxalyl chloride (0.3 ml, 3.01 mmol) in 5 ml of toluene was stirred for 3 hours at 35-40° C. and then at room temperature overnight. The mixture was then concentrated in vacuo to provide a yellow oil which was dissolved in 5 ml of CH2Cl2, cooled to 0° C. and treated with 2-chloroaniline. The resultant mixture was stirred at 0° C. for 2 hours and filtered. The filtrate was then washed sequentially with 1.0N HCl, NaHCO3 and brine, dried over Na2SO4, filtered and then concentrated in vacuo to provide a white solid (0.66 g, 92%). A portion of this solid was recrystallized (hexanes/CH2Cl2) to provide a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@H:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@@H:30]([CH:33]([CH3:35])[CH3:34])[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: CC(C)[C@@H](N)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@H](C(C)C)CO4)c3)cc12
Yield: 26.4 %

Procedure:
Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and (R)-2-amino-3-methylbutan-1-ol (111 mg, 1.08 mmol) in PhCl (3 mL) at rt. It was subjected for two interations to microwave irradiation for 1 hr at 200° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (13 mg, 25%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1H, s), 7.93-7.99 (2H, m), 7.89-7.93 (2H, m), 7.86 (1H, d, J=7.63 Hz), 7.63-7.69 (2H, m), 7.56 (1H, t, J=7.78 Hz), 7.26 (2H, t, J=8.55 Hz), 4.52 (1H, t, J=9.31 Hz), 4.30 (1H, t, J=8.09 Hz), 4.14-4.22 (1H, m), 2.98 (3H, s), 1.87-1.97 (1H, m), 1.04 (3H, d, J=7.02 Hz), 0.97 (3H, d, J=6.71 Hz). LC-MS retention time 1.64 min; m/z (MH+): 457. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=10.13 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=10.58 min, purity=94%.
Reaction SMILES: C(OC([N:8]([CH2:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[CH:22][CH:21]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[C:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[O:25])=[CH:33][CH:34]=2)[CH2:14][CH2:13]1)([CH3:17])([CH3:16])[CH3:18]
Reactant: COC(=O)C(C)NC(=O)c1ccc(CN(C(=O)OC(C)(C)C)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)NC(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl trans-4-{[N-(tert-butoxycarbonyl)-N-(4-tert-buylcyclohexyl)amino]methyl}benzoylaminopropanoate (19.5 g, 41.1 mmol) was dissolved in a mixture of TFA (200 mL) and dichloromethane (200 mL), while cooling on an ice bath. The ice bath was removed and the mixture allowed to stir at room temperature for 30 min. Solvent was removed by rotary evaporation, and the crystalline residue recrystallized from ethyl acetate/heptane. Yield: 14.8 g (74%).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:33])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1
Reactant: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCNS(C)(=O)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCN(C)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
4-(4-Bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propoxy)quinazoline (1.0 g, 2 mmol) was taken up in DMF (10 ml), treated with sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) and stirred, under nitrogen for 30 minutes. Methyl iodide (0.16 ml, 2.6 mmol) was added and the mixture stirred for 18 hours. The solvent was removed by evaporation and the residue taken up in water and extracted with dichloromethane (3×30 ml). The organic solution was then washed with water, brine, dried (MgSO4) and evaporated to dryness. The crude product was purified by silica column chromatography eluting with methanol (2.5 to 5%) in dichloromethane to give 4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methyl N-methylsulphonylamino) propoxy)quinazoline (0.86 g, 83%).