Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2([CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[C:4](=O)[NH:3][C:2]1=[O:16].[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[NH:1]1[C:5]2([CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:16]
Reactant: O=C1NC(=O)C2(CCC3(CC2)OCCO3)N1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C1NCC2(CCC3(CC2)OCCO3)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A suspension of 9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecane-2,4-dione (9.64 g, 42.6 mmol) in 143 mL of dry THF was treated at 0° C. with a solution of LiAlH4 1M in THF (94.0 mL, 94.0 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. An aqueous saturated solution of Rochelle's salt was added. It was stirred for 3 h, extracted 4× with EtOAc and 3× with dichloromethane. Organic portions were combined and concentrated. The crude was purified by silica gel column chromatography using a gradient from 1% CH2Cl2:MeOH to 10% CH2Cl2:MeOH as eluent to afford 9,12-Dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (5.20 g, 57%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(F)c1Nc1ccccc1
Agent: [Pd]
Product: Nc1cccc(F)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
A mixture of (2-fluoro-6-nitrophenyl)phenylamine (558 mg, 6.57 mmol) and 10% Pd/C (115 mg) in IMS (20 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 2 h. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo affording 3-Fluoro-N2-phenylbenzene-1,2-diamine as a white solid (468 mg, 96%). 1H NMR (CDCl3, 400 MHz): δ 7.24-7.16 (2H, m), 7.04-6.96 (1H, m), 6.83 (1H, t, J=7.37 Hz), 6.66 (2H, d, J=7.95 Hz), 6.59-6.48 (2H, m), 5.16 (1H, bs), 3.96 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24][NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: O=Cc1c(F)cccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1cc(-c2cccnc2)nn1-c1ccc(NCc2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) in acetic acid (2 mL) and MeOH (6 mL) at room temperature was added 2-chloro-6-fluorobenzaldehyde (79 mg, 0.5 mmol), followed by sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under a stream of nitrogen. The residue was diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution and water, and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel (eluent, gradient of 20-30% EtOAc in CH2Cl2) to provide the title compound (103 mg, 51%). NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.7 (br, 1H); 8.3 (d, 1H); 7.6-7.5 (overlapping m, 3H), 7.6-7.5 (overlapping m, 4H), 7.05 (m, 1H); 6.9 (d, 2H), 4.6 (s, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[Cl-].[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:21]=[C:20]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][C:1]([CH3:2])=[O:3])=[CH:8][CH:9]=1)[CH2:19][CH2:18][CH2:17][C:16]([O:15][CH3:14])=[O:23]
Reactant: COC(=O)CCCC(=O)O
Reactant: CC(=O)NCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCCC(=O)c1ccc(CCNC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 26.9 g. (0.165 mol) acetylphenethylamine (preparation see J. Am. Pharm. Assoc., 47, 353/1958) in 300 ml. methylene chloride is added dropwise first 30.0 g. (0.182 mol) glutaric acid methyl ester chloride and then 66.1 g. (0.495 mol) aluminium chloride are added portionwise thereto at 0° to 5° C. The reaction mixture is further stirred for 1 hour at 0° C., then allowed to warm up to ambient temperature and after 4 hours the reaction mixture is poured on to ice/hydrochloric acid. The organic phase is separated off, washed neutral with water and dried over anhydrous sodium sulphate. After stripping off the solvent, there are obtained 34 g. (71% of theory) of colourless crystals; m.p. 107°-108° C., after recrystallisation from ethyl acetate.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[I:18]I.[N+]([O-])(O)=O>C(Cl)(Cl)Cl>[C@@H:1]1([N:10]2[CH:17]=[C:16]([I:18])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: II
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)cc1I
Yield: 61.8 %

Procedure:
A mixture of 15 (1.2 g, 4.9 mmol), iodine (1.50 g, 5.9 mmol), CHCl3 (6 mL), and 1 N HNO3 (24 mL) was heated at reflux for 2 hours, and then cooled. The crystalline solid was collected by filtration and washed with ether to give the title compound 16 as a white solid (1.12 g, 62%). 1H NMR (DMSO-d6) δ 11.6 (s, 1H, NH), 8.10 (s, 1H, H-6), 5.95 (d, 1H, H-1′), 5.52 (br, 1H, OH), 5.40–5.10 (br, 1H, OH), 4.15–3.90 (m, 2H, H-2′, H-3′), 3.80–3.60 (m, 3H, H-4′, H-5′), 3.60–3.30 (m, 1H, OH).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH:16][CH2:17][C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)=[N:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.[CH3:37][N:38]([CH2:40][CH2:41]Cl)[CH3:39]>CN(C=O)C>[CH3:37][N:38]([CH3:39])[CH2:40][CH2:41][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:8]2[O:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH:16][CH2:17][C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)[C:15]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(-c2oc3ncnc(NC[C@@H]4CCCO4)c3c2-c2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-c2oc3ncnc(NC[C@@H]4CCCO4)c3c2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 28 %

Procedure:
A mixture of 80 (80 mg, 0.21 mmol), Cs2CO3 (0.12 g, 0.36 mmol) and N,N-dimethylaminoethyl chloride hydrochloride (59.4 mg, 0.41 mmol) in DMF (2 mL) was heated to 80° C. overnight. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography, to give 81 (27 mg, >95% e.e.). MS: 459.3 (M+1). 1HNMR (DMSO-d6) ppm 8.32 (s, 1H), 7.61-7.52 (m, 5H), 7.36 (d, 2H, J=9.00 Hz), 6.93 (d, 2H, J=9.00 Hz), 5.06 (t, 1H, J=5.50 Hz), 4.05 (t, 2H, J=6.00 Hz), 3.87-3.85 (m, 1H), 3.54-3.47 (m, 4H), 2.61 (t, 2H, J=5.50 Hz), 2.21 (s, 6H), 1.82-1.65 (m, 3H), 1.39-1.25 (m, 1H).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:33]=[CH:32][N:13]([C@@H:14]2[O:31][C@H:28]([CH2:29][OH:30])[C@@H:26]([OH:27])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](=[O:34])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[C:38]([O:57][CH3:58])=[C:39]([CH:54]=[CH:55][CH:56]=1)[C:40](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([NH:9][C:10]1[CH:33]=[CH:32][N:13]([C@@H:14]2[O:31][C@H:28]([CH2:29][O:30][C:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:39]3[CH:54]=[CH:55][CH:56]=[C:37]([O:36][CH3:35])[C:38]=3[O:57][CH3:58])[C@@H:26]([OH:27])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](=[O:34])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 96.7 %

Procedure:
N4-Benzoyl-2'-O-nonylcytidine (2.67 g, 0.0056 mol) was treated with dimethoxytrityl chloride (2.0 g, 1.1 eq) as per the procedure of Example 72 to give 4.2 g of pure product. Anal. Calcd. for C46H53N3O8.1/2H2O: C, 70.39; H, 6.93; N, 5.35. Found: C, 71.20; H, 6.88; N, 5.41.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:30])[CH:24]=2)[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([CH3:30])[CH:24]=5)[N:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COc1cc(Cl)nc2ccc(C)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc2ccc(C)cc12
Temperature: 150 °C

Procedure:
A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (58 mg, 0.267 mmol), 2-chloro-6-methyl-4-(methyloxy)quinoline (WO 99/55677) (56 mg, 0.027 mmol) and cesium carbonate (260 mg, 0.801 mmol) in dry DMF (3 ml) was heated at 150° C. for 2×30 mins. (300 W) in a microwave reactor. The cooled reaction mixture was partitioned between ethyl acetate (3×20 ml) and water (30 ml). The combined organic layers were washed with brine (2×30 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the resulting residue by column chromatography on silica gel, eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (E227); MS (ES+) m/e 389 [M+H]+.
Reaction SMILES: [CH:1](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:20].[Na+].OO>C(O)C>[CH2:17]([O:16][C:14]([C:8]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:20]1)=[O:15])[CH3:18]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)OC1c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
50 g of benzylidenemalonic acid, diethyl ester, (E. H. Kroeker, et al., J. Am. Chem. Soc., 56, 1171-3 (1934)) and 10 ml of 10% aqueous sodium bicarbonate were mixed with 100 ml of ethanol. 42 ml of 30% hydrogen peroxide was added dropwise over a 5-hour period at 70° C. Then 30 ml of 30% hydrogen peroxide was added over a one-hour period at 60° C. 100 ml of ethanol was added and the mixture was stirred for 8 hours at 60° C. The solvent was evaporated and the residue was extracted with methylene chloride. The solvent was evaporated from the separated extract and the residue was distilled to give ethyl 2-(ethoxycarbonyl)-3-phenyloxiranecarboxylate (6A), as a fraction boiling at 178°-180° C. at 0.05 Torr.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C[O:7][CH2:8][C:9]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][CH:36]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)[N:38]=3)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)([C:15]([O:17][CH2:18]C)=O)[C:10](OCC)=[O:11].[OH-].[Na+].Cl>C(O)C.C(OCC)C.O>[CH3:18][O:17][CH2:15][C:9]1([O:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][CH:36]=[C:37]([C:39]5[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=5)[N:38]=4)=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[C:10](=[O:11])[NH:5][C:3](=[O:4])[NH:2][C:8]1=[O:7]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(COC)(Oc1ccc(Oc2ccc(-c3nc(-c4ccc(F)cc4)co3)cc2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: COCC1(Oc2ccc(Oc3ccc(-c4nc(-c5ccc(F)cc5)co4)cc3)cc2)C(=O)NC(=O)NC1=O
Yield: 9.1 %

Procedure:
Sodium (210 mg, 9.1 mmol) was dissolved in dry ethanol (18 mL). Urea (328 mg, 5.46 mmol) and diethyl 2-(Methoxy-methyl)-2-{4-[4-(4-(4-fluorophenyl)-oxazol-2-yl)-phenoxy]-phenoxy}-malonate (1.0 g, 1.82 mmol) were added and the solution refluxed for 6 hours. The cooled mixture was diluted with ethyl ether and was with water and 2N sodium hydroxide solution. The combined aqueous layers were acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Filtration and concentration gave 179 mg of crude product which was chromatographed yielding 86 mg of the title compound as a white solid. LC-MS (m/z, APCI): 518 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[Cl-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)cc1-c1ccc(F)cc1
Yield: 98.3 %

Procedure:
Tetrakis(triphenylphosphine) palladium (9 g; 7.8 mmol) and ethanol (780 ml) was added to a suspension of methyl 4-methyl-2-trifluoromethanesulphonyloxybenzoate (58 g; 0.195 mol), 2M aqueous solution of sodium carbonate (250 ml; 0.5 mol), 4-fluorophenylboronic acid (30 g ; 0.214 mol) and lithium chloride (16.5 g ; 0.39 mol) in toluene (1.65 ml), under an argon atmosphere, The mixture was refluxed for 4 hours, diluted with ethyl acetate (1 l) and washed with aqueous sodium hydroxide solution 1N (1 l). The organic phase was evaporated and the residue purified by flash column chromatography using ethyl acetatelpetroleum ether (95:5) to give methyl 2-(4-fluorophenyl)-4-methylbenzoate (46.8 g; 99%).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.CO.[CH2:59]([N:66]1[CH2:70][CH:69]=[C:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O>[CH2:59]([N:66]1[CH2:70][C@H:69]([C:51]2[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=2)[C@@H:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CO
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Temperature: 60 °C
Yield: 9.7 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (185 mg, 0.05 eq.), (R)-BINAP (442 mg, 0.05 eq.) and 4-fluoro-phenylboronic acid (4.87 g, 2.5 eq.). 300 mL of MeOH and 30 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (2.8 g). The reaction mixture was heated at 60° C. for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 0.40 g (10%) of the title product as a light yellow oil. ES-MS m/e: 298.2 (M+H+).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:46]([C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][C:52]=3[OH:58])=[N:47][NH:48][C:49]=2[CH3:50])=[CH:41][CH:40]=1>ClCCl>[Br:1][C:55]1[CH:56]=[C:51]([C:46]2[C:45]([C:42]3[CH:41]=[CH:40][C:39]([O:38][CH3:37])=[CH:44][CH:43]=3)=[C:49]([CH3:50])[NH:48][N:47]=2)[C:52]([OH:58])=[CH:53][C:54]=1[OH:57]
Reactant: [Br-]
Reactant: COc1ccc(-c2c(-c3ccc(O)cc3O)n[nH]c2C)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3cc(Br)c(O)cc3O)n[nH]c2C)cc1
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
Benzyltrimethylammonium tribromide (4.0 g, 10.2 mmol) was added portion-wise to a suspension of 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol (2.95 g, 10 mmol) in dichloromethane (50 ml) and the mixture stirred for ˜90 mins. The mixture washed with water (3×50 ml) and saturated aqueous sodium chloride solution (25 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale yellow solid. Crude product was purified by column chromatography, on silica, eluting with ethyl acetate/hexane (1:2) to give 4-bromo-6-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol (1.75 g)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([OH:19])=[C:17]2[C:12]([C:13](=[O:30])[C:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:15]([CH:20]([CH3:22])[CH3:21])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[C:33]([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:33])=[C:17]2[C:12]([C:13](=[O:30])[C:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:15]([CH:20]([CH3:22])[CH3:21])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1oc2c(O)c(OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(OCc2ccccc2)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 7-benzyloxy-3-(4-chlorophenyl)-8-hydroxy-2-isopropyl-chromen-4-one (3.01 g, 7.15 mmol) and iodomethane (1.17 g, 8.22 mmol) in N,N-dimethylformamide (60 ml) is added K2CO3 (1.98 g, 14.3 mmol). The reaction mixture is stirred at room temperature for 72 h. The mixture is diluted with ethyl acetate and water, and the organic phase is washed with sodium thiosulfate solution and brine, dried (MgSO4) and concentrated in vacuo. The resulting off-white solid residue is triturated with ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: [N+:1]([CH:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH2:6][CH2:5]1)([O-])=O>C(O)C.[Pd]>[C:9]1([C@H:8]2[CH2:7][CH2:6][CH2:5][C@H:4]2[NH2:1])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])C1CCC=C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H]1CCC[C@@H]1c1ccccc1

Procedure:
(5-Nitro-cyclopent-1-enyl)-benzene (0.63 g, 3.3 mmol) from preparation 4 above, was hydrogenated in 25 mL of ethanol using 0.16 g of 5% Pd/C at room temperature overnight at 413.69 kPa (60 psi). The solution was filtered over celite and concentrated in vacuo to 230 mg (43%) of the title compound as a colorless oil. The NMR was consistent with the assigned structure. Mass Spectrum (ES MS): M+1=162.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[N:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(F)nc2)C1
Temperature: 110 °C
Yield: 68.4 %

Procedure:
Dissolve (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.49 g, 8 mmol) in toluene (20 mL). Heat to 110° C. and add 5-bromo-2-fluoropyridine (824 μL, 8 mmol), cesium carbonate (3.9 g, 12 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (748 mg, 1.2 mmol) and tris(dibenzylidineacetone)dipalladium(0) (733 mg, 0.8 mmol). Place a nitrogen inlet and condenser on the flask and heat at reflux overnight. Cool and filter the reaction mixture through a pad of Celite® and wash the pad with dichloromethane. Concentrate and chromatograph twice on silica gel, eluting with 0:100 to 25:75 ethyl acetate:dichloromethane, then 10:90 to 40:60 ethylacetate:hexanes, to give (S)-[1-(6-fluoropyridin-3-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester as a brown solid (1.54 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NOC(CCCC=O)C2)cc1OC
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2=NOC(CCCCN3CCN(c4ccccc4OC)CC3)C2)cc1OC
Yield: 67.2 %

Procedure:
4-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]butanal (26.7 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 26.5 mg (62.5%) of the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6]1)=[O:4].C(N(CC)CC)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C1COCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:33]([C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=3)(=[O:35])=[O:34])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)N1CCC(c2cccc(N)c2)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)c2)C1
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 3-(3-amino-phenyl)-pyrrolidine-1-carboxylic acid methyl ester (500 mg, 2.27 mmol) and triethylamine (500 mg, 4.94 mmol) in THF (20 ml) at 10° C. 4-trifluoromethoxy-benzenesulfonylchloride (600 mg, 2.3 mop was added. The mixture was allowed to come to room temperature and was stirred for 16 h. The mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over MgSO4 and evaporated under reduced pressure to give the product as a brown oil (1 g, 99%).