Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:27](OC3C=CC([N+]([O-])=O)=CC=3)=[O:28])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[CH2:44][CH2:43][CH:42]([C:45]#[N:46])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:45]([CH:42]1[CH2:43][CH2:44][N:39]([C:27]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:28])[CH2:40][CH2:41]1)#[N:46]
Reactant: N#CC1CCNCC1
Reactant: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1

Procedure:
115 mg (0.22 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxylate were initially charged in 3 ml of DMF, and 72 mg (0.65 mmol) of piperidine-4-carbonitrile and 30 mg (0.22 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 30 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 53 mg (48% of theory)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH3:18])[CH:14]([CH3:17])[CH2:15][CH3:16])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH3:18])[CH:14]([CH3:17])[CH2:15][CH3:16])[N:12]=1
Reactant: CN(C)C=O
Reactant: CCC(C)N(C)c1cncc(Cl)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)N(C)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Phosphoryl chloride (1.33 mL) was added dropwise to DMF (5 mL) at 0° C. The mixture was stirred for 15 min, and a solution of 6-chloro-N-methyl-N-(1-methylpropyl)pyrazin-2-amine (1.43 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 80° C. for 18 hr, water (5 mL) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10'50% ethyl acetate/hexane) to give the title compound (1.43 g, 88%) as a pale-yellow oil.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][CH2:7]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:7]1
Reactant: O=C1Nc2ccccc2OCC1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NC1COc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
A suspension of 1.85 g of 3-phthalimido-2,3-dihydro-1,5-benzoxazepin-4(5H)-one in 60 ml of absolute ethanol is treated with 0.31 ml of hydrazine hydrate and the reaction mixture is heated to reflux for 1.5 hr. After cooling to room temperature, the solid is removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in chloroform and filtered and concentrated a second time to afford 3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; m.p. 65°-70°; NMR (CDCl3) δ 6.50-7.60 (m, 4), 3.60-5.30 (m, 3), 3.25 [d (broad), 1].
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:13].[C:14]12([CH2:24][C:25](O)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[N:11]=[C:10]([Cl:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:13])=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(Cl)c2ccccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(Cl)c2ccccc2c1=O

Procedure:
The product from Example 19A and adamantyl acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.76 (m, 12H) 1.96 (s, 3H) 2.05 (s, 2H) 7.92-8.20 (m, 3H) 8.37 (d, J=7.63 Hz, 1H) 11.20-11.50 (m, 1H); MS (ESI) m/z 372 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@H:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10]3)[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
(S)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.16 mmol, 50 mg) was dissolved in THF (2 mL) and triethylamine (0.299 mmol, 42 μL, 30 mg) followed by methanesulfonyl chloride (0.16 mmol, 18.4 mg) and the solution stirred at room temperature overnight. The reaction was concentrated before partitioning between dichlormethane (3 mL) and 1N HCl (3 mL). The organic layer was collected and dried using a hydrophobic frit and concentrated under a stream of nitrogen to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give (S)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)methanesulfonamide (32.1 mg, 0.082 mmol, 51.2%) MS (ESI): m/z [M+H]+ 390.0
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>>[C:14]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COC(=O)c1ccc2c(C(=O)C(C)C)c[nH]c2c1

Procedure:
Methyl 3-isobutyrylindole-6-carboxylate (618 mg) was prepared from methyl indole-6-carboxylate (500 mg) and isobutyryl chloride (0.84 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:16][CH:17]=[CH2:18])[CH2:10][C:11]([O:13]CC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+]>CO>[Si:1]([O:8][C@H:9]([CH2:16][CH:17]=[CH2:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CC[C@H](CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of ethyl 3(R)-(tert-butyldimethylsilyloxy)-5-hexenoate (4) (80.60 g, 295.8 mmol) in MeOH (500 mL) is added a 40% KOH solution (150 mL). The mixture is stirred for 2 hours at 40° C. After the mixture is cooled to ambient temperature and MeOH is removed under reduced pressure (20 mbar) at 42° C., the obtained brown solid is dissolved in H2O (700 mL). The solution is washed with t-BuMeO (1×340 mL+3×215 mL) and then acidified with 4N HCl (222 mL) to pH=2. The yellow oil that separated from the water is extracted into t-BuMeO (6×110 mL). The combined organic layers are washed with water and dried (MgSO4). Ether is removed completely under reduced pressure (15 mbar) at 40° C. to give an orange-red oily residue (68.2 g, 94.3%). This residue is filtered two times through a thin pad of silica using t-BuMeO as solvent to afford (R)-3-(tert-butyldimethylsilyloxy)-5-hexenoic acid (5) (67.1 g, 93%) as yellow oil (GC purity 97.3%). 1H NMR (300 MHz, CDCl3): δ 11.03 (br s, 1H), 5.80 (ddt, J=17.8, 9.5 and 7.2 Hz, 1H), 5.13−5.11 (m, 1H), 5.08−5.06 (m, 1H), 4.20 (quint., J=6.5 Hz, 1H), 2.54 (dd, J=15.1 and 5.1 Hz, 1H), 2.46 (dd, J=15.1 and 7.1 Hz, 1H), 2.33−2.28 (m, 2H), 0.88 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 178.1, 133.8, 118.1, 68.8, 42.0, 41.8, 25.7, 17.9, −4.5, −5.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[CH:14]>C(N(CC)CC)C.[Pd](Cl)Cl.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[C:14][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CCCc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C#CC(C)(C)O)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
60 g of 1-bromo-4-propylbenzene, 38 g of 3-methyl-1-butyn-3-ol, 1.3 g of triphenylphosphine and 0.7 g of bis(triphenylphosphine) palladium(II) chloride were dissolved in 260 ml of triethylamine in nitrogen atmosphere, and 0.2 g of copper(I) iodide was added thereto. This was stirred for one hour at room temperature and for 5 hours at 90° C. The crystals as precipitated were filtered out and, after triethylamine was removed by distillation, extracted with chloroform. These were washed two times with 10% hydrochloric acid and two times with water, and chloroform was removed by distillation. The residue was purified by silicagel-chloroform column chromatography to obtain 37 g of 3-methyl-1-(4'-propylphenyl)-1-butyn-3-ol.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:18][CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CCO>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[O:17][CH2:18][CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 4-(tert-butyldimethylsilyloxy)-3-ethoxybenzaldehyde (12.7 g, 45.4 mmol, 1.0 equiv.) in EtOH (50 mL), NaBH4 (868 mg, 22.7 mmol, 0.5 equiv.) was added at 0° C., and the mixture was stirred at 0° C. for 2 h. After slow addition of sat. aq. NaHCO3-solution, the aqueous layer was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated to yield 12.6 g (98%) of (4-(tert-butyldimethylsilyloxy)-3-ethoxyphenyl)methanol as a light yellow oil.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:7]=1[CH2:26][NH:27][C:28](=[O:30])[CH3:29].[OH-].[Na+].[ClH:33]>[Cu]Cl>[Cl:33][C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:7]=1[CH2:26][NH:27][C:28](=[O:30])[CH3:29]
Reactant: CC(=O)NCc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CC(=O)NCc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1Cl
Reaction time: 0.67 h

Procedure:
To an aqueous solution (2 ml) of sodium nitrite (213 mg) was added a solution of N-(2-amino-4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)acetamide (1.1 g) in conc. hydrochloric acid (5 ml) under ice-cooling. This mixture was stirred at the same temperature for 40 min. The reaction mixture was added to a solution of copper(I) chloride (183 mg) in conc. hydrochloric acid (2 ml) over 10 min. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a green oil (1.4 g). The obtained green oil was purified by silica gel column chromatography (developing solvent ; chloroform:methanol=20:1) to give a pale-brown solid (0.9 g). This pale-brown solid was crystallized from ethyl acetate/hexane to give the title compound (0.75 g) as yellow crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]([C:31]3[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=3)=[CH:9][C:10]=2[C:11]([NH:13][CH:14]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][NH:16]C(=O)OC(C)(C)C)=[O:12])=[CH:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:16][CH2:15][CH:14]([NH:13][C:11]([C:10]1[CH:9]=[C:8]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[S:7][C:6]=1[C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:12])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)Cc2ccccc2)c(-c2ccoc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1cc(C(=O)NC(CN)Cc2ccccc2)c(-c2ccoc2)s1
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl [2-({[2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part e) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue passed through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]=[CH:12][CH:13]2OCC[O:14]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C>C(O)C.[Pd]>[CH2:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][CH2:12][CH:13]=[O:14])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](C=CC2OCCO2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCC[C@H]1CC[C@H](CCC=O)CC1
Temperature: 80 °C

Procedure:
The crude trans-4-butyl-1-[2-(1,3-dioxolan-2-yl)-vinyl]cyclohexane obtained is dissolved in 500 ml of ethanol, treated with 1 ml of triethylamine and 1 g of palladium/carbon (5%) and hydrogenated while shaking. After completion of the hydrogen uptake, the mixture is filtered and the residue is rinsed with 100 ml of ethanol. The filtrate is concentrated to half volume on a rotary evaporator, treated with 300 ml of water and 5 ml of concentrated sulphuric acid and heated to 80° C. for 30 minutes. For the working-up, the mixture is diluted with water, neutralized with sodium hydrogen carbonate and extracted twice with 250 ml of tert.butyl methyl ether each time. The organic phases are dried over sodium sulphate and freed from solvent on a rotary evaporator. The crude product of 3-(trans-4-butylcyclohexyl)propanal obtained is distilled in a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:22]1[NH:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28].C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28]
Reactant: COC(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nc(C)c(I)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(-c2[nH]c(C)nc2C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To methyl 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 50.2, 600 mg, 2.02 mmol) in dioxane (20 mL) was added 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5, 538 mg, 2.42 mmol) and Pd(dppf)Cl2.DCM (165 mg, 0.20 mmol). The mixture was degassed with argon and stirred for 10 minutes at room temperature, then an aqueous potassium carbonate solution (1M, 10 mL) was added and the mixture was stirred at 90° C. for 18 h. The mixture was cooled and diluted with EtOAc, then filtered through Celite®. The filtrate was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-100% EtOAc in hexanes) to yield 270 mg (50%) of the title compound as a foam. m/z (ES+) 265 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8.4, 2.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][CH2:40]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:48][C:46]1[C:45]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:44][C:43]2[C@@:10]3([CH2:40][O:41][C:42]=2[CH:47]=1)[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 7.1 %

Procedure:
To a solution of 29 (60 mg, 0.77 mmol) in a mixture of MeOH (2.4 mL) and THF (0.8 mL) were added Pd(OH)2/C (25 mg) and 1,2-dichlorobenzene (60 μL). A balloon of hydrogen gas was attached for 0.5 hours with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory TLC (5% MeOH in DCM) to give 30 (23 mg, 71.2%). 1H NMR (300 MHz, CD3OD) δ 7.18 (s, 1H), 7.07 (s, 4H), 6.82 (s, 1H), 4.68 (d, J=10.2 Hz, 1H), 4.59 (d, J=9.9 Hz, 1H), 3.99 (m, 2H), 3.59-3.80 (m, 3H), 3.28-3.37 (m, 3H), 2.58 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1](OCC)=[O:2].[NH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:1]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: CCOC=O
Reactant: C1CCCNCC1
Product: O=CN1CCCCCC1
Reaction time: 8 h
Yield: 84 %

Procedure:
Ethyl formate (22.2 G, 0.3M) was added dropwise under nitrogen to hexahydro-1H-azepine (19.8 G, 0.2M) in such a way that a gentle reflux is maintained during the addition. The reaction mixture was then allowed to stir overnight. The volatile materials were evaporated at room temperature and ~20 mm. The residue was distilled in vacuo to give 1-(Formyl)-Hexahydro-1H-Azepine (bp. 56°-8°/3-4 mm; 84%).
Reaction SMILES: B.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:8][CH:7]=[CH:6]2.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C1COCC1.O>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][CH2:7][CH2:6]2
Reactant: Fc1cc2cc[nH]c2cc1-c1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Fc1cc2c(cc1-c1ccccc1)NCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A mixture of 6-bromo-5-fluoro-1H-indole (0.214 g, 1 mmol), phenylboronic acid (0.171 g, 1.4 mmol), sodium carbonate (1.06 g, 10 mmol), Pd(PPh3)4 (0.116 g, 0.1 mmol), 1,2-dimethoxyethane (5 mL) and water (5 mL) was stirred under nitrogen at 85° C. for 18 h. The mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-50% Et2O in petrol) gave 5-fluoro-6-phenyl-1H-indole (0.202 g, 95%) as a pale green solid. MS: [M+H]+=212. A solution of borane in THF (1 M, 1.42 mL) was added to 5-fluoro-6-phenyl-1H-indole (0.20 g, 0.95 mmol) under nitrogen with external cooling using an ice-MeOH bath. The resulting mixture was stirred at 0° C. for 0.5 h, then TFA was added dropwise over 0.1 h. The mixture was stirred at 0° C. for 1 h then a solution of sodium hydroxide (0.8 g, 20 mmol) and water (5 mL) was added dropwise over 0.1 h. The resulting mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% Et2O in petrol) gave the title compound (0.17 g, 85%) as an oil. MS: [M+H]+=214.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=1[F:31]>C(Cl)Cl>[F:31][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:20]=1[NH:19][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)cc1F

Procedure:
A solution of hexadecanoyl chloride (20 g) in 100 ml of methylene chloride is slowly added with stirring to a solution of 20 g of ethyl 4-amino-3-fluorobenzoate in 100 ml of methylene chloride. The mixture is filtered and the filtrate is washed with dilute hydrochloric acid and water, dried and the solvent evaporated. Crystallization of the residue from acetonitrile affords ethyl 3-fluoro-4-(hexadecanoylamino)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CC(C)=O>[N:10]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1ccc(Cl)cc1

Procedure:
A solution of 4-chlorobenzyl bromide in acetone was treated with NaN3 and refluxed for 3 hours. The reactions was concentrated by 50% and diluted with saturated sodium chloride solution. The reaction was then extracted with Et2O, washed with brine, dried (Na2SO4) and concentrated to give 1-(azidomethyl)-4-chlorobenzene.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([S:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N2C[C@H](CN3CCC(Sc4ccc(Cl)cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: Clc1ccc(SC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-chlorophenylthiopiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 233°-236°; [α]D =-30.8° (DMSO);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([NH:14]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.C(OCC)(=O)C>[Pd].CO>[CH3:1][O:2][C:3](=[O:25])[CH:4]([NH2:14])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1
Reactant: COC(=O)C(=Cc1ccc(OC)nc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(N)Cc1ccc(OC)nc1
Reaction time: 8 h

Procedure:
A flask containing 2-benzyloxycarbonylamino-3-(6-methoxy-pyridin-3-yl)-acrylic acid methyl ester (620 mg), palladium on charcoal (10%, 100 mg), ethyl acetate (10 mL) and methanol (20 mL) was flushed with nitrogen, then hydrogen, before finally affixing a balloon of hydrogen. The reaction was allowed to stir overnight. The flask was flushed with nitrogen, filtered through celite, and concentrated to give 390 mg (quant.) which was used without purification. Mass spec.: 211.11 (MH)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][C:16]([NH2:21])=[N:15][C:14]=2[N:13]([CH2:22][C:23]2[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=2)[CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][C:16]([NH2:21])=[N:15][C:14]=2[N:13]([CH2:22][C:23]2[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=2)[CH:12]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCNC(=O)OC(C)(C)C)c3c(Cl)nc(N)nc32)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2cc(C#CCN)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of {3-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (see previous example, 22 mg) in DCM (3 mL) was treated with TFA (0.6 mL) at rt for 15 min. Evaporation, work-up (DCM/sat. aq. NaHCO3), drying (Na2SO4), and evaporation gave the title compound as an oil. tR=3.85 min. 1H NMR (CDCl3) δ 8.24 (s, 1H), 7.06 (s, 1H), 5.32 (s, 2H),5.02 (s, 2H), 3.75 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H).