Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:14])[NH:8]OC(C)(C)C.C1(C)C=C(C)C=C(C)C=1S([N:46]1C=NC([N+]([O-])=O)=N1)(=O)=O.CN1C=CN=C1>C(Cl)Cl>[NH2:1][C@H:2]([C:15]([NH2:46])=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:14])[NH2:8]
Reactant: Cc1cc(C)c(S(=O)(=O)n2cnc([N+](=O)[O-])n2)c(C)c1
Reactant: CC(C)(C)ONC(=N)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cn1ccnc1
Solvent: ClCCl
Product: N=C(N)NCCC[C@H](N)C(N)=O
Reaction time: 0.08 h

Procedure:
Fmoc-Arg(OtBu)-OH, 1-mesitylenesulfonyl-3-nitro-1,2,4-triazole (MSNT) and N-methylimidazole were dissolved in CH2Cl2, and the solution was stirred for 5 minutes and thereafter placed into the solid-phase synthesis column containing the resin, followed by stirring at room temperature for 3 hours. The resin was thereafter washed with methylene chloride, isopropanol and DMF and dried. The unreacted hydroxyl group on the solid phase was thereafter acetylated using a 20% DMF solution of acetic anhydride for 20 minutes for capping. The resin was washed with DMF and stirred along with a 20% piperidine/DMF solution for 20 minutes to remove the protective Fmoc group, whereby resin-Arg-NH2 was obtained. The product was washed with DMF and dried.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:21].Cl.[N:23]1([C@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:21])=[C:2]([N:30]4[CH2:31][CH2:32][C@H:28]([N:23]5[CH:27]=[CH:26][N:25]=[N:24]5)[CH2:29]4)[N:11]=3)[C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cn([C@H]2CCNC2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CC[C@H](n4ccnn4)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 24.2 %

Procedure:
Ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (250 mg, 0.8 mmol) was reacted with 350 mg (2 mmol) of 3(S)-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 8 ml of pyridine in the presence of 305 mg (2 mmol) of DBU at 80°-90° C. for 6 h. The reaction was then stirred at r.t. for 4 days. The solvent was then evaporated under reduced pressure and to the residue, water was added and extracted with chloroform. The organic layer was dried and evaporated to dryness. The residue was then chromatographed over alumina (neutral, activity III) using chloroform as solvent to yield 80 mg (24%) of the desired product. 1H NMR (CDCl3) δ: 8.48 (s, 1H), 8.05 (d, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 5.46-5.32 (m, 1H), 4.46-4.26 (m, 4H), 4.15-4.0 (m, 2H), 3.56-3.42 (m, 1H), 2.71-2.57 (m, 2H), 1.4 (t, 3H), 1.26-0.95 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15](C)[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([C:27]3[CH:28]=[CH:29][C:30]([N+:37]([O-:39])=[O:38])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])=[O:26])=[N:23][CH:24]=2)[CH:21]=1)=O)(C)(C)C>ClCCl>[CH3:13][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([C:27]3[CH:28]=[CH:29][C:30]([N+:37]([O-:39])=[O:38])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])=[O:26])=[N:23][CH:24]=2)[CH:21]=1
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccc(N(C)C(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc2cnc(C(=O)c3ccc([N+](=O)[O-])c(C(=O)OC)c3)n2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
1.3 ml of trifluoroacetic acid are added to 460 mg (1.01 mmol) of methyl 5-({6-[(tert-butoxycarbonyl)(methyl)amino]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-nitrobenzoate in 5 ml of dichloromethane and the mixture is stirred at ambient temperature overnight. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and basified with a saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. 350 mg of a red powder are obtained. Melting point: 183° C.; 1H NMR (d6-DMSO): 2.79 (3H, d), 3.90 (3H, s), 7.11 (1H, d), 7.77 (1H, s), 7.82 (1H, d), 8.31 (1H, d), 8.66 (1H, d), 8.75 (1H, s), 9.01 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][NH:18][CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:10])=[O:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNCc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-chloro-2-hydroxybenzaldehyde (1.5 g 9.3 mmol), tert-butylcarbazate (1.25 g, 9.3 mmol) and acetic acid (0.54 mL, 9.3 mmol) in CH2Cl2 (50 mL) was stirred under a nitrogen atmosphere for 30 min at RT. Then sodium triacetoxyborohydride (6.20 g, 27.9 mmol) was added portion wise and the resulting mixture was stirred at RT overnight. The reaction was thoroughly quenched with 2 M HCl (15 mL) and stirred at RT for 1 h. The reaction mixture was partitioned between water (50 mL) and CH2Cl2 (25 mL). The aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic layers were washed with water (2×75 mL), dried (Na2SO4) and evaporated to dryness to give hydrazine 1 as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:8][CH2:9][P:10]([CH2:15][N:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:14])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:36](Br)[CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:24]1([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][CH:15]([P:10]([CH:9]([N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:31][CH:30]=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:14])[O:11][CH2:12][CH3:13])[CH2:36][CH:37]=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)CN=C(c1ccccc1)c1ccccc1
Reactant: BrCC=Cc1ccccc1
Product: CCOP(=O)(C(CC=Cc1ccccc1)N=C(c1ccccc1)c1ccccc1)C(CC=Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Yield: 76 %

Procedure:
Analogously to example 6, the bis-alkylated phosphinates 8 were prepared in a yield of 76% from the protected phosphinate 3 and cinnamyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]#[C:15][CH2:16][CH3:17])[CH2:6][O:7][NH2:8].C(N(C(C)C)C(C)C)C.[Cl:27][C:28]1[CH:38]=[CH:37][C:31]([CH:32]([OH:36])[C:33](O)=[O:34])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:32]([OH:36])[C:33]([NH:8][O:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]#[C:15][CH2:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:34])=[CH:37][CH:38]=1
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Reactant: CCC#CCOc1ccc(CON)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC#CCOc1ccc(CONC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Reaction time: 16 h

Procedure:
O-(3-methoxy-4-pent-2-ynyloxy-benzyl)-hydroxylamine (5.0 g, 21 mmol) and N-ethyldiisopropylamine (Hünig's base, 5.5 g, 42 mmol) are dissolved in 60 ml of N,N-dimethylformamide. 4-chloro-DL-mandelic acid (4.1 g, 22 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, Castro's reagent, 10 g, 23 mmol) are added successively and the mixture is stirred for 16 h. After pouring the mixture on ice/water, it is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The remaining oil is purified by chromatography on silica gel (ethyl acetate/hexane (4:6)) to obtain 2-(4-chloro-phenyl)-2-hydroxy-N-(3-methoxy-4-pent-2-ynyloxy-benzyloxy)-acetamide as yellow resin.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+].OO>C1COCC1>[C:9]1([CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][OH:24])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CCOCCCCc1ccccc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCOCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of Intermediate 11 (0.40 g, 2.10 mmol) in THF (5 mL) was cooled to 0° C. A 0.5 M solution of BBN (5 mL, 2.52 mmol) in THF was added, and the resulting mixture was stirred 1 hour at 0° C. and 2 hours at room temperature. A solution of 2M NaOH (1 mL) and hydrogen peroxide (1 mL, 35%) was successively added and the mixture stirred 1 hour at room temperature. The solution was then concentrated and the residue dissolved in ether (25 mL), washed with water (2×15 mL) and brine (5 mL), dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel (hexane/AcOEt, 6:1) afforded the title compound (0.24 g, 55%) as oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[Zn+]>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:25]2[S:24][CH:28]=[CH:27][N:26]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Zn+]c1nccs1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Agent: [Br-]
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2nccs2)n1

Procedure:
Was prepared according to Example 5 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and 2-thiazolylzinc bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([N:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])[CH:6]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)[CH:8]=1.FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([N:50]([CH3:52])[CH3:51])(=[O:48])=[O:49])[CH:6]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:8]=1
Reactant: COc1cc(NS(=O)(=O)N(C)C)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N(C)C)cc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 93 %

Procedure:
N′-[3-Methoxy-5-(4-{[(1S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]-N,N-dimethylsulfamide (30 mg, 0.03 mmol, 85% purity) was treated with trifluoroacetic acid (600 μl, 7.79 mmol) and a solution of ammonia (7N in methanol, 600 μl, 4.20 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 23 mg (93% yield, 85% purity) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride. A solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil. To 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) as refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° D.). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+]>C(O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3cccc(OC)c3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (197 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-[{[4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL), 1N lithium hydroxide (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (216 mg, 91%).
Reaction SMILES: [Si:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[CH2:29])[C:19]([O:21]CC3C=CC=CC=3)=[O:20])=[CH:14][C:13]=2[F:30])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[Si:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:29])[C:19]([OH:21])=[O:20])=[CH:14][C:13]=2[F:30])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(C(=O)OCc1ccccc1)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a stirred solution of crude benzyl 2-(4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-3-fluorophenyl)acrylate (4.14 g) in EtOAc (30 mL) was added 20% Pd(OH)2 (207 mg, 5% moleq.) and stirred under hydrogen gas balloon at RT for 1 h. The Pd(OH)2 was filtered out, filtrate evaporated and resulting residue was purified by silica gel (neutral, 100-200) column using ethyl acetate/PE (3:17) as eluent to get crude 2-(4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-3-fluorophenyl)propanoic acid (1.8 g, 64% LC-MS, HPLC purity) as off white solid. The crude product on prep HPLC purification provided (1.23 g, 13% yield over 3 steps). [TLC system: EtOAc/PE (1:5), Rf: 0.6].
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].F[C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Nc1cccc(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1cccc(F)c1
Yield: 93.3 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (21 mL, 53 mmol), diisopropylamine (7.2 mL, 51 mmol), 3-fluoro-aniline (1.6 mL, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.0 g, 17 mmol) provided 4.24 g of the crude title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl-quinoline.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1cc[n+]([O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccnc(Cl)c1

Procedure:
5.0 g (36.5 mmol) of 4-acetyl-pyridine N-oxide and 6.64 ml (73 mmol) of phosphorus oxychloride are stirred in 50 ml of toluene for 2 h at 100°. The reaction mixture is stirred at 50° into 500 ml of 10N sodium hydroxide solution, extracted with ethyl acetate and treated with Tonsil (Fluka; bentonite--colloidal aqueous aluminium silicate). Concentration and crystallisation (diethyl ether/n-hexane) give 4-acetyl-2-chloro-pyridine;
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[N+:25]([C:28]1[CH:41]=[CH:40][C:31]([C:32]([O:34][C@H:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>C(#N)C>[N+:25]([C:28]1[CH:41]=[CH:40][C:31]([C:32]([O:34][C@H:35]2[CH2:39][CH2:38][N:37]([CH2:6][CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH2:36]2)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]
Reactant: O=C(O[C@H]1CCNC1)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 90 °C

Procedure:
3-(4-Methoxyphenyl)propyl mesylate (732 mg, 3.00 mmol), sodium carbonate (320 mg, 3.00 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to a solution of (S)-3-(4-nitrobenzoyloxy)pyrrolidine (472 mg, 2.00 mmol) in acetonitrile (25 ml), and they were heated under reflux at 90° C. for 6 hours. The solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-(4-nitrobenzoyloxy)-1-[3-(4-methoxyphenyl)propyl]pyrrolidine in the form of a light yellow oil (507 mg, 66%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([C@H:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1.[CH2:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>N1C=CC=CC=1>[F:18][C:14]1[CH:13]=[C:12]([F:19])[CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][C@H:8]([N:7]1[C:3]([CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)=[CH:4][NH:5][C:6]1=[S:20])[CH2:9]2
Reactant: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)NCc2c[nH]c(=S)n2[C@H]2CCc3c(F)cc(F)cc3C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A mixture of (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.30 g, I mmol), prepared as in Example 31, and 4-butylbenzoyl chloride (0.21 mL, 1.1 mmol) in 10 mL of dry pyridine was stirred under argon at approximately 0° C. for 1 hour and then at approximately 25° C. for an additional 2 hours. The mixture was concentrated and the residue was treated with water. The mixture was extracted with ethyl acetate (3x) and the combined extracts were dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to give (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]-4-butylbenzamide (0.25 g, 0.55 mmol), m.p. 242°-243° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[P:5]([Cl:8])(Cl)[Cl:6].[CH3:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[CH3:16]>>[CH3:9][C:10]1[CH:11]=[C:12]([P:5]([Cl:8])[Cl:6])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: ClP(Cl)Cl
Reactant: Cc1ccccc1C
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(P(Cl)Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A mixture of carefully dried o-xylene (29.9 g), freshly prepared anhydrous aluminium trichloride (56 g) and freshly distilled phosphorus trichloride (172.6 g) was refluxed gently, with stirring, for 2 hours. The mixture was then refluxed vigorously for a further 11/2 hours. The source of heat was removed and freshly distilled phosphoryl chloride (64.5 g) added to the mixture dropwise, with stirring, so that reflux was maintained; a white solid precipitated during the addition. The reaction mixture was allowed to cool to room temperature and dry pentane (100 ml) was added and the resultant mixture stirred for several hours, after which the precipitated solids were filtered off and washed with dry pentane. Volatile products were removed from the combined filtrates under reduced pressure, and the resulting yellow oil was fractionally distilled under reduced pressure. The required product 3,4-dimethylphenyl phosphonous dichloride (58 g) was distilled at a pressure of 0.05 mmHg at 78°-80° C. This was equivalent to a yield of 65.6% based on o-xylene. It was a colourless liquid.