Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[F-].[K+]>C1(C)C=CC=CC=1>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
To a solution of 1-bromo-4-nitro-benzene (2.02 g, 10 mmol) in toluene (20 mL) is added palladium tetrakis triphenylphosphine (1.156 g, 1 mmol), 4-t-butyl phenyl boronic acid (3.56 g, 20 mmol), and potassium fluoride (1.74 g, 30 mmol). The reaction is purged with nitrogen three times and heated to reflux under nitrogen. At the reflux temperature, water (5 mL) is added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is, diluted with ethyl acetate and Celite® is added, followed by water. This mixture is then filtered through a pad of Celite®. The solution is poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified by flash column chromatography, eluting with ethyl acetate/hexanes to afford 1.8 g of the product as a yellow solid. 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:19](#[N:21])[CH3:20]>>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:20][C:19]#[N:21])[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(OCc2c(Cl)cccc2Cl)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCc2c(Cl)cccc2Cl)c1

Procedure:
Addition of acetonitrile to 3-(2,6-Dichlorobenzyloxy)benzaldehyde gave 3-[3-(2,6-dichlorobenzyloxy)phenyl]-3-hydroxypropionitrile as a yellow oil. Yield (1.65 g, 68%): 1H NMR (400 MHz, CDCl3) δ 7.34-7.39 (m, 3H), 7.24-7.28 (m, 1H), 7.07 (s, 1H), 7.00-7.05 (m, 2H), 5.29 (s, 2H), 5.04 (t, J=6.4 Hz, 1H), 2.78 (d, J=6.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2OC)=[N:10]O)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)[C:22](OC(=O)C(F)(F)F)=[O:23].C(N(CC)CC)C.O>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[N:7]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:23][CH3:22])=[CH:16][CH:17]=3)[CH:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(Cc1cccc(Cl)n1)=NO
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl[Fe]Cl
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 51.6 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(methoxyphenyl)ethanone oxime (38.7 g, 140 mmol) in 1,2-dimethoxyethane (156 mL) at 0° C. was added trifluoroacetic anhydride (20 mL, 140 mmol), keeping the temperature below 10° C. during the addition. After the addition was complete, the reaction was warmed to 15° C. The solution was then cooled to 4° C. and a solution of triethylamine (39 mL, 280 mmol) in 1,2-dimethoxyethane (15 mL) was added over a period of 0.5 hours. The mixture was allowed to warm to room temperature and was stirred at room temperature for 1.5 hours. To this mixture was added iron(II) chloride (0.18 g, 1.4 mmol) and the reaction was heated at 75° C. for 15 hours. The reaction mixture was poured into water (300 mL). The resulting suspension was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was recrystallized from methanol to give 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine (18.7 g, 52%) as pale yellow needles. 1H NMR (CDCl3): δ 7.91 (d, 2H), 7.43 (d, 1H), 7.01 (t,1H), 6.95 (d, 2H). 6.81 (d,1 1H), 6.80 (s, 1H), 3.83 (s, 3 H); MS m/z 259 (M+1).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]=[N:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@H:36]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[F:59])=[CH:48][CH:47]=1)[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([F:59])=[C:52]([C:49]2[CH:48]=[CH:47][C:46]([CH2:45][C@@H:36]([NH:35][C:8]([C:6]3[N:5]=[N:4][N:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40])=[CH:51][CH:50]=2)[CH:57]=1
Reactant: COn1cc(C(=O)O)nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.3 %

Procedure:
1-Methoxy-1H-[1,2,3]triazole-4-carboxylic acid (4.3 mg, 30 μmol) and HATU (11.4 mg, 30 μmol) were combined in DMF (1 mL) and stirred at room temperature for 15 minutes. (2S,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (10 mg, 27 μmol) and DIPEA (14 μL, 82 μmol) were added, and the resulting mixture was stirred for 15 minutes at room temperature. The solvent was removed in vacuo and the residue was purified by preparative HPLC to yield the title compound (1.1 mg). MS m/z [M+H]+ calc'd for C23H24ClFN4O5, 491.14. found 491.2.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@H:11]1[CH2:20][C:19]23[CH2:21][CH2:22][C@:12]1([OH:47])[CH:13]1[O:30][C:28]4=[C:29]5[C@@:14]12[CH2:15][CH2:16][N:17]([CH2:43][CH:44]1[CH2:46][CH2:45]1)[C@@H:18]3[CH2:23][C:24]5=[CH:25][CH:26]=[C:27]4OC1N(C2C=CC=CC=2)N=NN=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.O.NN>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH2:1]([NH:8][C:9]([C@H:11]1[CH2:20][C:19]23[CH2:21][CH2:22][C@:12]1([OH:47])[CH:13]1[O:30][C:28]4=[C:29]5[C@@:14]12[CH2:15][CH2:16][N:17]([CH2:43][CH:44]1[CH2:45][CH2:46]1)[C@@H:18]3[CH2:23][C:24]5=[CH:25][CH:26]=[CH:27]4)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)[C@H]1CC23CC[C@]1(O)C1Oc4c(Oc5nnnn5-c5ccccc5)ccc5c4[C@@]12CCN(CC1CC1)[C@@H]3C5
Agent: [Pd]
Agent: NN
Solvent: c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)[C@H]1CC23CC[C@]1(O)C1Oc4cccc5c4[C@@]12CCN(CC1CC1)[C@@H]3C5
Temperature: 85 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
Under an argon atmosphere, the compound 112 (2.33 g, 3.69 mmol) was dissolved in ethanol (20 mL), benzene (36 mL), and water (10 mL), the solution was added with 10% palladium-carbon (2.3 g), and aqueous hydrazine (64 v/v %, 25 mL), and the mixture was stirred at 85° C. for 16 hours. The reaction mixture was diluted with ethyl acetate, and filtered through Celite. The organic layer was washed with water, and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The obtained crude product was purified by silica gel column chromatography to give the title compound 113 (650 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[CH3:42][CH:43]([NH2:53])[CH2:44][CH2:45][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:53][CH:43]([CH3:42])[CH2:44][CH2:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[O:17])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(N)CCCc1cccnc1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc(C(=O)NC(C)CCCc3cccnc3)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
A solution of 50 g of 3',4'-dimethyl[1,1'-biphenyl]-4-carboxylic acid in 200 mL of DMF was cooled in an ice bath and 5.2 mL of diphenylphosphoryl azide was added. After 20 minutes, 3.9 mL of triethylamine was added, and after a further hour, 4.0 g of rac. alpha-methyl-3-pyridinebutanamine was added and the mixture was allowed to warm to room temperature over night. The solvent was evaporated, the residue was taken up in dichloromethane and washed with water and bicarbonate, dried (MgSO4), and purified by preparative hPlc eluting with 95:5 dichloromethane-methanol to give 4.1 g (65%) of rac.-3',4'-dimethyl-N-[1-methyl-4-(3-pyridinyl)butyl][1,1'-biphenyl]4-carboxamide, mp 118°-120° C. after recrystallization from ethyl acetate-hexane. The analytical sample was obtained from ethyl acetate. mp 120°-121° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:15][Mg]Br.C(OCC)C.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:7](=[O:8])[CH3:15])[CH:13]=1
Reactant: CON(C)C(=O)c1cc(Br)ccc1F
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 97 %

Procedure:
To a stirred solution of compound 14 (106 g, 404 mmol) in anhydrous THF (1.7 L) was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 270 mL, 808 mmol) at 0° C. under nitrogen. After addition was completed, the reaction mixture was stirred at 0° C. for 6.5 h. After this time, the solution was poured to a cold 2 N hydrochloric acid (1 L) and warmed to room temperature. The resulting mixture was extracted with ethyl acetate (2×1 L). The combined extracts were washed with saturated aqueous NaHCO3 (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 15 (85.2 g, 97%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.98 (dd, J=6.4, 2.6 Hz, 1H), 7.61 (ddd, J=8.7, 4.3, 2.6 Hz, 1H), 7.05 (dd, J=10.4, 8.7, 1H), 2.64 (d, J=4.9, 3H); ESI MS m/z 217 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=1.O>C1COCC1>[F:7][C:8]1[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[C:10]([O:18][CH3:19])[CH:9]=1
Reactant: COC(=O)c1ccc(F)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)ccc1CO
Reaction time: 1 h
Yield: 83 %

Procedure:
To a suspension of LiAlH4 (94.6 mg, 2.49 mmol) in THF (3 ml) was added dropwise a solution of methyl 4-fluoro-2-methoxybenzoate obtained in Example 23-2) (273.3 mg, 1.48 mmol) in THF (3 ml). The mixture was stirred for 1 hour. To the mixture was added dropwise aqueous THF followed by water. The mixture was extracted three times with ethyl acetate and dried over MgSO4. The solvent was evaporated to give the crude title compound (310.8 mg; 83%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:19]([NH2:21])[CH3:20]>N1C=CC=CC=1.CCO>[CH3:20][O:19][N:21]=[C:1]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-benzoyl phenyl boronic acid (226.00 mg, 1.00 mmol) and methoxyl amine hydrochloride (101.00 mg, 1.20 mmol) in pyridine (5 mL) and EtOH (5 mL) was refluxed at 125° C. for 24 h. Reaction was then concentrated in vacuo to give a crude product which was used for next step without further purification. MS (ES+): m/z 256.00 (100)[MH+]. HPLC: tR=3.17 min (Open Lynx polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:30].[NH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:30]
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NC(CO)CO
Product: O=c1ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F

Procedure:
The product of Example 57, and serinol were reacted by the procedure of Example 60 to afford the title compound, 8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 2.52 (br s, 2H), 3.45 (m, 1H), 3.60 (m, 4H), 6.28 (br s, 1H), 6.34 (d, 1H, J=9.7 Hz), 6.98 (m, 2H), 7.19 (m, 3H), 7.42 (m, 3H). LC MS (m/e)=443 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: O=Cc1cc(OC2CCCCO2)ccc1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 15.6 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (10 g, 49.75 mmol) and 3,4 dihydro-2H-pyran (4.96 mL, 54.7 mmol) in CH2Cl2 (35 mL) was added camphorsulfonic acid (230 mg, 0.99 mmol), and the mixture was stirred at room temperature for 21 h. The reaction mixture was then quenched with equal volumes of 0.2 M NaOH and EtOAc (1:1, 70 mL) before the layers were separated. The water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-bromo-5-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (2.22 g, 20%).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH:18]([CH2:28][NH:29]C(=O)C(F)(F)F)[CH2:17]3)=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:29][CH2:28][CH:18]1[CH2:17][N:16]([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:21][CH2:20][N:19]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27]
Reactant: O=C(NCC1CN(C2=Nc3ccccc3Sc3ccccc32)CCN1CCOCCO)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NCC1CN(C2=Nc3ccccc3Sc3ccccc32)CCN1CCOCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-((4-(dibenzo[b,f][1,4]thiazepin-11-yl)-1-(2-(2-hydroxyethoxy)ethyl)piperazin-2-yl)methyl)-2,2,2-trifluoroacetamide, prepared as described in the previous step, (2.0 g) and aqueous potassium carbonate (5%) (15 mL) in methanol (20 mL) was stirred at room temperature for 18 hours and extracted with ethyl acetate. The organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, evaporated to give the crude product which was purified by column chromatography, and followed by prep-HPLC to provide the title compound as a yellow solid. ESI-MS (M+1): 413 calc. for C22H28N4O2S 412. 1H NMR: (CDCl3, 400 MHz): δ (ppm) 7.52-7.50 (m, 1H), 7.41-7.31 (m, 4H), 7.17-7.12 (m, 1H), 7.02-7.00 (m, 1H), 6.89-6.84 (m, 1H), 3.66-3.59 (m, 5H), 3.54-3.51 (m, 2H), 3.49-3.38 (m, 1H), 3.19-3.12 (m, 1H), 3.03-2.88 (m, 2H), 2.79-2.53 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]2=[O:18])=[N:6][CH:7]=1.[CH3:19][C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:19][C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C@H:25]1[CH2:29][CH2:28][N:27]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:12][CH2:11][C:10]4([CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:9]3=[O:18])=[N:6][CH:7]=2)[CH2:26]1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: O=C1N(c2ccc(Br)cn2)CCC12CCOCC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N3CCC4(CCOCC4)C3=O)nc2)C1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(5-bromo-pyridin-2-yl)-8-oxa-2-aza-spiro[4.5]decan-1-one (0.05 g, 0.161 mmol), (2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl (0.037 g, 0.242 mmol), (−)R-BINAP (0.006 g, 0.01 mmol), and anhydrous toluene (3 mL) was de-gassed and refilled with N2 in three cycles. Pd2(dba)3 (0.003 g, 0.0032 mmol,), and sodium t-butoxide (0.023 g, 0.242 mmol) was then added to the mixture and de-gassed and refilled with N2 in three additional cycles. The reaction mixture was heated and stirred at 90° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and quenched with water (1 mL). The aqueous phase was extracted with dichloromethane (3×10 mL). The combined organics were washed with sodium bicarbonate (5 mL), and brine (10 mL), dried over Na2SO4, concentrated under vacuum. Purification by column chromatography on silica gel (0-10%) methanol in dichloromethane afforded 0.0349 (56%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:23])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(Br)c3O2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccccc4)c3O2)cc1
Yield: 93 %

Procedure:
Treatment of 2-bromo-4-methylphenol (19.09 g, 102 mmol) with potassium carbonate (56.0 g, 400 mmol) and allyl bromide (15.96 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-methylphenol. Treatment of 2-allyl-6-bromo-4-methylphenol (5.21 g, 23.0 mmol) with 3-chloroperoxybenzoic acid (9.13 g, 34.50 mmol, 77%) followed by potassium carbonate (7.9 g, 57.5 mmol) generally according to the procedure described for Intermediate 9 afforded 2.14 g (43%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (2.41 g, 10.0 mmol) with p-toluenesulfonyl chloride (2.1 g, 11.0 mol) generally according to the procedure described for Intermediate 10 gave 3.31 g (84%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.25 g, 0.63 mmol) and phenylboronic acid (0.23 g, 1.89 mmol) generally according to the procedure described for Intermediate 154 afforded 0.23 g, (93%) of (±)-(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.15 g (97%) of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.297 g, 1.13 mmol) according to the procedure described in Example 21 afforded 0.106 g (61%) of (±)-[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 227-228° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[NH2:15][C:16]1[C:21]2[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[C:26]([NH:25][C:23]1[S:24][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:13])[C:21]=2[N:22]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1nc2c(N)cccc2s1
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Product: CC(=O)Nc1nc2c(NC(=O)c3ccc4cc(Br)ccc4c3)cccc2s1

Procedure:
This material was prepared analogous to the procedure described for Example 1(b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), (98 mg, 0.36 mmol) reacted with N-(4-amino-benzothiazol-2-yl)-acetamide (50 mg, 0.24 mmol, prepared according to the procedure described in WO03099284) to give the title compound as a solid. Mp 241.6° C. MS (ESI, pos. ion.) m/z: 441 (M+1).
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][CH:5]=1)C.[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].O>C(O)(=O)C>[N:7]1[C:8]2[C:13](=[CH:12][C:11](/[CH:14]=[C:22]3/[C:20](=[O:21])[NH:19][C:17](=[S:18])[S:16]/3)=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CSC(=S)N1
Reactant: CCOc1ccnc2ccc(C=O)cc12
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)S/C1=C\c1ccc2ncccc2c1
Temperature: 25 °C
Yield: 115.7 %

Procedure:
The suspension of 4-ethoxy-quinoline-6-carbaldehyde (example 3b) (4.0 g, 20 mmol) and rhodanine (2.65 g, 20 mmol) in acetic acid (40 mL) was stirred under reflux for 12 h. After cooling to room temperature, water (50 mL) was added. The solid was collected by filtration, washed with water and dried to obtain 5-[1-quinolin-6-yl-meth-(Z)-ylidene]-2-thioxo-thiazolidin-4-one (6.3 g, 100%) as a brown solid. LC-MS m/e 317 (MH+).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18]N[CH2:16][CH2:15]1)(C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C=C.C(=O)([O-])[O-:25].[Na+].[Na+]>O1CCCC1>[CH2:15]([N:14]([CH2:19][CH3:18])[C:1](=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of benzhydrylpiperazine epimers (7.6 g, 14.9 mmol) was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL (18.6 mmol) of allyl bromide and 5.1 g (36.9 mmol) of sodium carbonate and stirred at room temperature under nitrogen for 2 days. The reaction solution was poured into ice water/ethyl acetate and separated. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and placed on a column of silica gel. The diastereomers were separated by elution with a stepwise gradient of ethanol in dichloromethane. The first isomer was eluted with 1.3% ethanol in dichloromethane, and the second isomer was obtained with 1.6% ethanol in dichloromethane. Fractions containing the second isomer were combined and the solvent removed in vacuo to give 1.44 g of 4-(αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a brown oil.