Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH2:12][CH2:11]2)=[O:5].[Cl:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:19][C:8]1[CH:9]=[C:10]2[C:14](=[C:6]([C:4](=[O:5])[C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=3[F:1])[CH:7]=1)[NH:13][CH2:12][CH2:11]2
Reactant: O=C(c1ccccc1F)c1cccc2c1NCC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=C(c1ccccc1F)c1cc(Cl)cc2c1NCC2
Yield: 84 %

Procedure:
44 g (182 mmol) of 7-(2-fluorobenzoyl)indoline and 800 ml of methylene chloride are poured into a reactor equipped with a central stirrer, a condenser provided with a calcium chloride guard tube, a dipping thermometer, a nitrogen inlet and a pressure-equalizing dropping funnel. 27.9 g (182 mmol) of N-chlorosuccinimide are added gradually and the mixture is stirred over a warm temperature. The mixture is washed with saturated sodium bicarbonate solution and then with water, dried and evaporated. It is chromatographed on silica, eluting with methylene chloride. 42 g (84% yield) are obtained. The product is obtained in the form of a foam which has no definite melting point. TLC: H2CCl2Rf=0.70.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C[Al](C)C.C([O:14][C:15]([C:17]1[S:21][C:20](/[CH:22]=[CH:23]/[C:24]2[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:26][O:27][C:28]=2[CH3:29])=[N:19][CH:18]=1)=O)C>O1CCOCC1.C1(C)C=CC=CC=1>[O:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:15]([C:17]2[S:21][C:20](/[CH:22]=[CH:23]/[C:24]3[C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:26][O:27][C:28]=3[CH3:29])=[N:19][CH:18]=2)=[O:14])[CH2:3][CH2:4]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)NC2CCOCC2)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a stirred solution of 4-aminotetrahydropyran (123 mg, 1.22 mmol) in dioxane (3 mL) under argon and at room temperature was added trimethylaluminium (0.6 mL of a 2M solution in toluene, 1.2 mmol). After 1 h, a solution of 2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid ethyl ester (50 mg, 0.15 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. for 3 h. The reaction mixture was then cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 2.5% methanol in dichloromethane) gave the title compound (34 mg, 59%) as a white solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:25])[C:9]=1[O:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH:5]=[O:6].[CH2:26]([C@H:33]1[CH2:37][O:36][C:35](=[O:38])[N:34]1[C:39](=[O:44])[CH2:40][O:41][CH2:42][CH3:43])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC>>[CH2:26]([C@H:33]1[CH2:37][O:36][C:35](=[O:38])[N:34]1[C:39](=[O:44])[C@@H:40]([O:41][CH2:42][CH3:43])[C@@H:5]([C:4]1[CH:3]=[C:2]([CH3:1])[C:9]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[C:8]([CH3:25])[CH:7]=1)[OH:6])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCc1nc(-c2ccccc2)oc1C
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (example 117) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-3-hydroxy-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-3-}3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-3-hydroxy-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-ethoxy-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralpak-AD) to be 98.8%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: O=C1CCc2cc(F)ccc21
Solvent: c1ccncc1
Product: O=C1CCc2cc(N3CCCCC3)ccc21

Procedure:
5-Fluoroindan-1-one (5 g, 33.3 mmol) and piperidine (8.52 g, 100 mmol, 10 ml) were dissolved in pyridine (20 ml) and heated to reflux for 3 hours. The reaction mixture was cooled, the solvent removed under vacuum, and the residue taken in diethyl ether. The ether solution was washed with 1N aqueous sodium hydroxide and with water, dried with magnesium sulfate, filtered, and the filtrate was removed under vacuum to provide the title compound which was used without further purification. 1H NMR (CDCl3) δ 1.67 (m, 6H), 2.63 (m, 2H), 3.02 (m, 2H), 3.40 (m, 4H), 6.78 (d, 1H), 6.86 (dd, 1H), 7.62 (d, 1H); MS (DCI) 216 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)=[CH:7][C:6]=2[CH:24]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=3)=[CH:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3cc(Cl)ccc3s2)CC1
Solvent: ClCCl
Product: Clc1ccc2sc(C3=CCNCC3)cc2c1
Yield: 65.4 %

Procedure:
A solution of 0.998 gm (2.72 mMol) 5-chloro-2-(4-hydroxy-1-(tert-butoxycarbonyl)piperidin-4-yl)benzothiophene in 10.0 mL dichloromethane was subjected to the reaction conditions described in the previous example, providing 0.444 gm (65%) of 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzothiophene as a tan solid. This material was dissolved in ethyl acetate and the solution was treated with oxalic acid. The resulting solution was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28].Cl>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([C:9]([F:11])([F:10])[F:12])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH2:17][N:16]([CH2:26][CH2:27][CH3:28])[CH2:15][CH2:14]1
Reactant: COc1c(C2CCNCC2)cccc1C(F)(F)F
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2OC)CC1

Procedure:
Preparation according to Example 1: 4-[2-methoxy-3-(trifluoro-methyl)phenyl]piperidine (0.38 g, 1.47 mmol), acetonitrile (40 ml), potassium carbonate (0.4 g, 3.7 mmol) and 1-iodopropane (0.115 ml, 1.47 mmol). Yield: 0.33 g (74%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 235.5° C. MS m/z (relative intensity, 70 eV) 301 (M+, 7), 273 (22), 272 (bp), 229 (6), 159 (13).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[C:10]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:11][CH:12]=1)[C:5](O)=[O:6].[NH2:33][CH:34]1[C:41](=[O:42])[N:40]2[CH:35]1[S:36](=[O:70])[CH2:37][C:38]([C:59]1[S:63][C:62]([C:64]3[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=3)=[N:61][CH:60]=1)=[C:39]2[C:43]([O:45][CH:46]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH:46]([O:45][C:43]([C:39]1[N:40]2[CH:35]([S:36](=[O:70])[CH2:37][C:38]=1[C:59]1[S:63][C:62]([C:64]3[CH:65]=[CH:66][N:67]=[CH:68][CH:69]=3)=[N:61][CH:60]=1)[CH:34]([NH:33][C:5](=[O:6])[C:4](=[N:3][O:2][CH3:1])[C:8]1[N:9]=[C:10]([NH:13][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=1)[C:41]2=[O:42])=[O:44])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CS(=O)C12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 7.5 %

Procedure:
The syn isomer of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid (12.4 g) and 4-N,N-dimethylaminopyridine (0.05 g) are added to a solution of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (15 g) in dry methylene chloride (100 cc), and a solution of N,N'-dicyclohexylcarbodiimide (6.93 g) in methylene chloride (120 cc) is then added (in the course of 30 minutes) after cooling to +5° C. The reaction mixture is then stirred for 1 hour at +5° C. and then for 4 hours at 25° C., after which it is partially concentrated, diluted again with ethyl acetate (500 cc) and filtered. The filtrate is poured into a mixture of distilled water (1 liter), ethyl acetate (1 liter) and acetic acid (10 cc). The organic phase is washed with a saturated solution of sodium bicarbonate (200 cc), distilled water (3×200 cc) and then a saturated solution of sodium chloride (200 cc), dried over sodium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give the crude expected product (26.8 g) in the form of a hard brown foam, which can be purified in the following manner: the crude product (5 g) is redissolved in ethanol (120 cc) under reflux, decolorising charcoal (0.5 g) and silica (0.5 g) are added, the mixture is stirred and filtered and the filtrate is cooled in a bath of iced water. The precipitate is filtered off and washed with ethanol (2×10 cc) and then ether (2×20 cc) to give 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia1-azabicyclo[4.2.0]oct-2-ene 5-oxide (2 g) in the form of an ochre powder.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.[CH:15]1[C:28]2[C:19](=[N:20][CH:21]=[C:22]3[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:18]=[CH:17][CH:16]=1>O>[Cl:3][C:25]1[CH:24]=[CH:23][C:22]2[C:27]([CH:26]=1)=[C:28]1[C:19]([CH:18]=[CH:17][CH:16]=[CH:15]1)=[N:20][CH:21]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)cnc1ccccc12
Solvent: CN(C)c1ccccc1
Solvent: O
Product: Clc1ccc2cnc3ccccc3c2c1
Yield: 96 %

Procedure:
Phosphorus oxychloride (15 ml) and dimethylaniline (0.63 ml) were added to phenanthridine (2.0 g), followed by refluxing for 3 hours. The solution was poured into H2O to generate a solid, and the obtained solid was extracted with chloroform, followed by drying with sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform) (amount: 2.1 g, yield: 96%).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26].O>CC(C)=O>[CH:1](=[N:8]/[O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)c1ccccc1CBr
Reactant: ON=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(O)c1ccccc1CO/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.8 %

Procedure:
Then, benzaldehyde oxime (0.28 g, 2.3 mmol) and potassium carbonate (0.43 g, 3.1 mmol) were added to a solution of methyl 2-bromomethyl-α-hydroxyphenylacetate (0.40 g, 1.5 mmol) in acetone (6 ml), and the mixture was stirred at room temperature for 18 hours. Water was added, and the mixture was extracted with ether, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/1) to give the desired compound methyl (E)-2-benzylideneaminooxymethyl-α-hydroxyphenylacetate (0.08 g, 17%) as an oil.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C@@H:17]2[CH2:18][C@@H:14]([CH:15]=[CH:16]2)[C@@H:13]1[C:19]([O:21][CH3:22])=[O:20])=O)C1C=CC=CC=1.[ClH:23].O1CCOCC1>C(OCC)(=O)C.[Pd].C(OCC)C>[ClH:23].[NH2:11][C@@H:12]1[C@@H:17]2[CH2:18][C@@H:14]([CH2:15][CH2:16]2)[C@@H:13]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)OCc2ccccc2)[C@H]2C=C[C@@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (1S,2S,3R,4R)-3-{[(benzyloxy)carbonyl]amino}bicyclo[2.2.1]hept-5-ene-2-carboxylate (1 g, 3.32 mmol) was dissolved in ethyl acetate (15 mL). 5% Palladium on carbon (120 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in diethyl ether (10 mL) and added dropwise, with vigorous stirring, to a mixture of 4.0 M hydrochloric acid solution in 1,4-dioxane (1.8 mL, 7.2 mmol) in diethyl ether (18 mL). The desired product began to precipitate as a white solid. Additional diethyl ether (10 mL) was added and the mixture was stirred for 10 min. The precipitate was collected by vacuum filtration and washed with additional diethyl ether (2×8 mL). The solid was further dried in vacuo for 1 h to afford the desired product, methyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (0.554 g, 2.7 mmol, 81%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.18-1.27 (3H, m), 1.37-1.61 (2H, m), 1.90 (1H, d, J=11.0 Hz), 2.35 (1H, d, J=3.8 Hz), 2.44 (1H, d, J=3.1 Hz), 2.75 (1H, d, J=8.7 Hz), 3.29-3.34 (1H, m), 3.61 (3H, s), 8.03 (3H, bs). LC-MS (ESI) calcd for C9H15NO2 (free amine) 169.11, found 170.3 [M+H+] (100%), 339.3 [2M+H+] (50%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH2:21])=[CH:8][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:24]=[C:25]2[CH2:31][CH2:30][NH:29][C:26]2=[N:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[C:1]([NH:5][C:6]1[C:7]([NH2:21])=[CH:8][C:9]([C:23]2[CH:24]=[C:25]3[CH2:31][CH2:30][NH:29][C:26]3=[N:27][CH:28]=2)=[CH:10][CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1cnc2c(c1)CCN2
Reactant: CC(C)(C)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1N
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1ccc(-c2cnc3c(c2)CCN3)cc1N
Temperature: 110 °C
Yield: 28.3 %

Procedure:
In a microwave vial are added N1-tert-Butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzene-1,2-diamine (100 mg, 0.5 mmol) and 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (180 mg, 0.62 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) and K2CO3 (139 mg, 1 mmol) in DMF (4 mL) and H2O (0.2 mL). The reaction mixture is heated at 110° C. in a microwave reactor for 1 hour. The reaction is cooled down to room temperature, poured into H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title intermediate (40 mg, 28%). LCMS (ESMS): m/z 283.20 (M++1)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.O>[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO[Si](C)(C)C(C)(C)C)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO)cc2)CC1
Temperature: 0 °C
Yield: 77.7 %

Procedure:
To a THF (8 mL) solution of tert-butyl 4-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethyl)benzyl]piperazine-1-carboxylate (0.96 g) was added 1.0 M solution of TBAF in THF (2.32 mL) at 0° C. The resultant mixture was stirred at room temperature for 2.5 hours. After cooling to 0° C., the reaction mixture was diluted with AcOEt and water. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=40/1) to afford tert-butyl 4-[4-(2-hydroxyethyl)benzyl]piperazine-1-carboxylate (0.55 g) as a colorless oil.
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3](C(OC(C)(C)C)=O)[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>CN(C=O)C>[CH3:39][C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][N:49]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[O:27])[CH2:48][CH2:47]2)=[CH:44][CH:45]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)C(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)OCC3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
(tert-Butoxycarbonyl)piperidin-4-ylmethyl 4-nitrophenyl carbonate (Intermediate 2; 3.80 g, 10.0 mmol) was dissolved in DMF (100 mL). DIPEA (6.10 mL, 35.0 mmol) and 4-(4-methylphenyl)piperazine dihydrochloride (2.49 g, 10.0 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The resulting residue was dissolved in EtOAc (300 mL) and washed with a 1 M aq Na2CO3 solution (6×200 mL), 10% citric acid solution (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a mixture of DCM (100 mL) and TFA (25 mL), stirred for 48 hours and then concentrated in vacuo. The residue was purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give piperidin-4-ylmethyl 4-(4-methylphenyl)piperazine-1-carboxylate (1.60 g, 44.6%) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])C.[Li+].[OH-]>C1COCC1.CO.O>[CH3:13][C:5]([CH3:14])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:4]([OH:15])=[O:3]
Reactant: C=CCCCCCC(C)(C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCCCCCC(C)(C)C(=O)O
Reaction time: 15 h
Yield: 93.6 %

Procedure:
A solution of 2,2-dimethylnon-8-enoic acid ethyl ester (51, 800 mg, 3.77 mmol) and LiOH (806 mg, 18.9 mmol) in THF/MeOH/water, 1:1:0.5, was heated at 50° C. for 2.5 h. Then, additional LiOH (1.60 g, 10 eq) was added. After 15 h, the reaction mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 3 with HCl 1N, extracted with CH2Cl2, washed with brine, dried (MgSO4), filtered and concentrated to give 650 mg (94%) of the title product (52) as a colorless oil.
Reaction SMILES: Br[C:2]1O[C:5]([CH2:7][N:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O)=[O:12].[C:22](=O)([O-])[O-].[Na+].[Na+].Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH3:9][N:8]([CH2:7][C:5]1[CH2:22][C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:11]=[O:12])=[CH:3][CH:4]=1)[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CN(C)Cc1ccc(Br)o1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CC1=CC=C(c2ccccc2C=O)C1
Temperature: 150 °C
Yield: 69 %

Procedure:
In a microwave vial, (5-bromo-furan-2-ylmethyl)-dimethyl-amine (385 mg, 1.88 mmol), 2-formyl phenylboronic acid (288 mg, 1.93 mmol) and 3.7 ml of actonitrile were mixed. Then, 3.7 ml of 1N aqueous sodium carbonate was added to the mixture, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, 20 ml of 1N HCl was added. The mixture was extracted by ethyl acetate (3×10 ml) and the ethyl acetate layer was discarded. 1N NaOH solution was added to aqueous phase to adjust pH to 10, then extracted with ethyl acetate (3×20 ml). The combined organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated to give 300 mg of 2-(4-dimethylaminomethyl-cyclopenta-1,3-dienyl)-benzaldehyde, yield: 69%.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:14][C:13]=1[CH3:31])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23]2)=[CH:14][C:13]=1[CH3:31]
Reactant: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A suspension of tert-butyl 4-(4-(((benzyloxy)carbonyl)amino)-3-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I52) (798 mg, 2.49 mmol) and 10% Pd/C (250 mg) in MeOH (50 mL) was stirred under hydrogen (1 atm) for 16 hours at room temperature. The resulting mixture was filtered through celite, washing with MeOH, then the volatiles were removed by evaporation under reduced pressure to give the title compound (I53) (550 mg, 76%) as a purple/brown liquid; 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J=6.7 Hz, 3H), 4.22 (s, 2H), 2.77 (s, 2H), 2.54 (s, 1H), 2.29 (s, 3H), 1.77 (d, J=12.7 Hz, 2H), 1.56 (dd, J=12.6, 3.7 Hz, 9H), 1.47 (s, 9H). LCMS Method C rt: 5.09 min; m/z 235.1 [M-tBu+2]+, 191.2 [M-Boc+2]+.