Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH4+].[NH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16]>>[NH2:10][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5].[NH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16]
Reactant: O=C([O-])/C=C\C(=O)O
Agent: NCCNCCN
Agent: [NH4+]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 0.67 h

Procedure:
Monoammonium maleate (2.993 g of 94% wet salt, 0.0212 mole) and diethylenetriamine(.[.0,115.]. 0.115 g, 0.0011 mole) were mixed together and reacted according to the procedure of Example 2 and 3 at .[.230° -255°.]. 230°-255° C. for 40 minutes. The resulting polysuccinimide-diethylenetriamine crosslinked copolymer weighed .[.1,970.]. 1.970 g. Hydrolysis of this product produced an aspartic acid-diethylenetriamine copolymer having molecular weights by GPC of Mw 5207, Mn 1359, Mw/Mn 3.83.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([N:3]1[C:2]([NH2:1])=[C:6]([C:7]#[N:8])[CH:5]=[N:4]1)[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: N#Cc1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1ncc(C#N)c1N
Temperature: 80 °C
Yield: 39.8 %

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Acros, 1.08 g, 10.0 mmol), allylbromide (Acros, 1.45 g, 12 mmol) and anhydrous potassium carbonate (Fisher, 1.65 g, 12 mmol) were suspended in 10 mL anhydrous DMF and heated at 80° C. under argon overnight. The solution was concentrated. Water was added (100 mL) and the organics were extracted with dichloromethane (3×100 mL). The combined dichloromethane fractions were washed with water (50 mL) and brine (50 mL) and were dried (magnesium sulfate). Concentration of the organics afforded a solid which was subjected to flash chromatography on silica gel (gradient elution 2:1 to 3:2 hexane:ethyl acetate). 589 mg (40%) of a white solid was obtained which was seen by NMR to contain an inseparable mixture of 5 and 6 in a 2.1:1 ratio. This mixture was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6]C(SC)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+].O.[CH3:18]S(C)=O>>[N+:1]([C:4]1[CH:5]=[N:6][C:12]([S:13]([CH3:18])(=[O:15])=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CSc1ccc([N+](=O)[O-])cn1
Reactant: CS(C)=O
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cn1
Temperature: 100 °C

Procedure:
Alternatively, 3-nitro-6-(methylsulfonyl)pyridine was prepared by dissolving of 3-nitro-6-(methylthio)pyridine (1 equivalent) and sodium methane sulfinate in DMSO and heating at 100° C. for 2 hours. The reaction was diluted with a large excess of water and extracted with ethyl acetate. The organic layer was concentrated in vacuo to give the desired 3-nitro-6-(methylsulfonyl)pyridine.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].Cl[Si:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH3:9][Si:8]([CH3:11])([CH3:10])[O:5][CH:4]=[CH:3][C:2]([CH3:6])=[CH2:1]
Reactant: CC(C)=CC=O
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C=CO[Si](C)(C)C

Procedure:
3-methyl-2-butenal is reacted with chlorotrimethylsilane using the method of P. Cazeau et al., Tetrahedron 43, 2075-2088 (1987), in acetonitrile containing triethylamine and anhydrous sodium iodide at 40°-45° to yield 1-trimethylsilyloxy-3-methyl-1,3-butadiene 2;
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+].O.O>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)C1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)C3CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
A solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) in DMF (0.2 mL) was added to a solution containing cyclopropanecarboxylic acid (24.8 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uranium tetrafluoroborate (101.7 mg, 0.32 mmol), N,N-diisopropyl ethyl amine (247 μL, 1.44 mmol) in DMF (0.3 mL) and the resulting mixture stirred at room temperature overnight and then heated at 110° C. for 2.5 h. The resulting mixture was then poured into a mixture of brine: water (1:1) and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a brown solid. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (12.4 mg, 12%) which was obtained as an off-white solid. MS: m/e 359.0 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH2:31])[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8].Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH:31][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccccn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 120 °C
Yield: 39 %

Procedure:
Sodium tert-butoxide (135 mg, 1.41 mmol)) was added to a suspension of ethyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 16) (450 mg, 1.28 mmol), 2-bromopyridine (403 mg, 2.55 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (40 mg, 0.102 mmol) and tris(dibenzyldieneacetone)dipalladium(0) (47 mg, 0.051 mmol) in anhydrous toluene (4.5 mL). The mixture was heated under microwave irradiation to 120° C. for 1 h in a sealed vial. The mixture was partitioned between EtOAc and water, the aqueous layer was extracted twice with EtOAc, the combined organic phases were dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue. The residue was purified by chromatography (10 g column, EtOAc/cyclohexane gradient followed by MeOH/EtOAc gradient) to give ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (216 mg, 0.503 mmol, 39% yield) as a brown gum. LCMS: (Formate, 2 min), Rt=0.84 min, MH+430.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[S:24]
Reactant: S=C=S
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: CCCCCCCCCCBr
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1CO

Procedure:
In the same manner as described in Example 29 by using (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g), triethylamine (1.67 ml), CS2 (0.72 ml), n-decyl bromide (2.65 g) and dimethylsulfoxide (10 ml), there is prepared the title compound (2,48 g, 59%) as colorless needles, m.p. 115°-118° C. (recrystallized from ether-n-hexane), [α]D20 +113.0° (c=1.0, methanol); NMR (CDCl3, δ): 0.95 (m, 3H, --CH3); Mass m/e: 418 (M+), 244 (M+ --C10H21SH).
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH3:9]C([OH:12])C.C(OCC)(OCC)OCC.[ClH:23]>O>[OH2:4].[OH2:12].[ClH:23].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: CC(C)O
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Solvent: O
Solvent: CCOC(OCC)OCC
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
Under the nitrogen atmosphere, 5.00 g of 2-aminomalonamide was added to 100 mL of 2-propanol. After heating to 80° C., 17.7 mL of triethyl orthoformate was added dropwise to the mixture over 30 minutes. Subsequently, the reaction mixture was stirred for 7 hours and 50 minutes at 83 to 84° C. Subsequently, after cooling to 50 to 60° C., the reaction mixture was added with an aqueous solution prepared with 4 mL of conc. hydrochloric acid and 5 mL of water. After cooling the mixture to 20 to 30° C., the crystal was collected by filtration and then washed with 25 mL of acetone to give 8.04 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a pale yellow crystal.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.Br.Br[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C(O)C>[CH3:28][N:29]1[CH2:34][CH2:33][C:32]2[N:9]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][C:7]=3[C:31]=2[CH2:30]1
Reactant: Cc1ccc(NN)cc1
Reactant: BrCCN1CCCC1
Reactant: CN1CCC(=O)CC1
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCN2CCCC2)CCN(C)C1
Yield: 4.8 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. 4-Methylphenylhydrazine hydrochloride (2 g, 12.6 mmol), 1-(2-bromoethyl)pyrrolidine hydrobromide (8.1 g, 31.5 mmol), triethyl amine (17.5 ml, 126 mmol) and N-methyl-4-piperidone hydrochloride (1.87 g, 12.6 mmol) were combined in ethanol (15 ml) to obtain 180 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrido[4,3-b]indole after on purification on silica gel (230-400 mesh) chromatography eluting with acetone-hexane gradient. The free base was converted into its dioxalate salt by treatment of oxalic acid (2 equiv.) in anhydrous THF.
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:61](#[N:64])[CH:62]=[CH2:63]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([N:4]([CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:63]=[CH:62][C:61]#[N:64])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:29]([CH3:31])[CH3:30])([CH3:3])[CH3:2]
Reactant: C=CC#N
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=CC#N)ccc1OCc1ccccc1)C(C)C
Temperature: 115 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (13.87 g, 28.87 mmol) (prepared as described in WO 94/11337, Example 1) in DMF (140 mL) was added triethylamin (5.00 mL, 36.10 mmol), Pd(OAc)2 (0.32 g, 1.44 mmol), tri(o-tolyl)phosphine (1.76 g, 5.77 mmol) and acrylonitrile (2.39 mL, 36.10 mmol). The reaction mixture was stirred overnight at 115° C. in a sealed flask equipped with a reflux condenser under nitrogen atmosphere. The resulting mixture was concentrated, and the residue was dissolved in diethyl ether, washed with aqueous 2 M sodium hydroxide and water. The organic phase was dried (MgSO4) where after petroleum ether was added to the organic phase and a precipitate was formed. Recrystallisation from ethanol yielded 5.50 g (42%). 1H NMR (CDCl3) δ0.90 (s, 6H), 0.95 (s, 6H), 2.15 (q, 2H), 2.35 (q, 2H), 2.95 (m, 2H), 4.40 (t, 1H), 5.05 (s, 2H), 5.70 (d, 1H), 6.85 (d, 1H), 7.10-7.50 (m, 13H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:22])([F:21])[C:12]1[C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:45]=[C:46]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[CH2:47][NH:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C.O>[O:45]=[C:46]([N:63]1[CH2:68][CH2:67][N:66]([C:18]([C:17]2[CH:16]=[N:15][CH:14]=[CH:13][C:12]=2[C:11]([F:10])([F:22])[F:21])=[O:20])[CH2:65][CH2:64]1)[CH2:47][NH:48][C:49]([C:51]1[CH:52]=[CH:53][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:55][CH:56]=1)=[O:50]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cnccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 4-trifluoromethyl-nicotinic acid (49.2 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 80% EtOAc in hexane as eluent) to afford 48 mg (47.6% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(4-trifluoromethyl-pyridine-3-carbonyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 94.74%, 1H NMR: (DMSO) δ 9.0-8.84 (d, 2H), 8.7-8.6 (t, 1H), 8.0 (d, 2H), 7.9 (d, 1H), 7.84-7.7 (q, 4H), 7.6-7.4 (m, 3H) 4.2 (d, 2H), 3.8-3.6 (d, 4H), 3.3-3.2 (s, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:26]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18]([O:20][CH3:26])=[O:19])=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CCCOc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: C1CCOC1
Product: COC(=O)C(C)(C)CCCOc1ccc(OCc2ccccc2)cc1

Procedure:
In 100 ml of tetrahydrofuran was dissolved 9 g of 5-(p-benzyloxyphenoxy)-2,2-dimethylpentanoic acid. The resulting solution was treated with a diazomethane-ether solution in a conventional manner to give methyl 5-(p-benzyloxyphenyloxy)-2,2-dimethylpentanoate. The thus obtained ester was dissolved in 200 ml of methanol and 10% palladium-carbon was added to the solution. The mixture was reacted with stirring in a hydrogen atmosphere under normal pressure until a theoretical amount of hydrogen was absorbed. Palladium-carbon was removed by filtration and the solvent was removed by distillation under reduced pressure to give the desired product, methyl 5-(p-hydroxyphenoxy)-2,2-dimethylpentanoate as crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C@@H:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:13]C(=O)OC(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:13][C@@H:3]1[CH2:4][C@H:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[C:2]1([CH3:21])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCCC2)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCCC1
Yield: 100 %

Procedure:
A solution of tert-butyl (1R,3S)-2,2-dimethyl-3-(pyrrolidine-1-carbonyl)cyclobutylcarbamate (step 1, 0.400 g, 1.351 mmol) in TFA:DCM (1:2) (3 ml) stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (1.124 ml, 8.108 mmol) the resulting solution as such used for next reaction immediately. Wt: 0.264 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[CH:27]1([CH2:30][N:17]2[CH2:18][CH2:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[CH2:15][CH2:16]2)[CH2:29][CH2:28]1
Reactant: O=CC1CC1
Reactant: O=C(Cc1cc(F)cc(F)c1)NCC1(c2ccc(I)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(F)cc(F)c1)NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1
Reaction time: 0.5 h
Yield: 950 %

Procedure:
To a stirred solution of 4-{[2-(3,5-difluoro-phenyl)-acetylamino]-methyl}-4-(4-iodo-phenyl)-piperidine (0.038 g, ˜0.08 mmol) in ClCH2CH2Cl (0.5 mL) at room temperature under Ar was added cyclopropanecarboxaldehyde (0.008 mL, 0.096 mmol, 1.2 eq.) and HOAc (0.05 mL, 1% v/v). The mixture was stirred for 0.5 h then Na(OAc)3BH (0.026 g, 0.12 mmol, 1.5 eq.) was added and the mixture stirred for 16 h then diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and dried under high vacuum to give N-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-2-(3,5-difluoro-phenyl)-acetamide (0.040 g, 0.76 mmol, 95%). MS (ESI): 525.2/526.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[F:14][C:15]1[CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22].[F-].[K+]>C(#N)C.O.C(OCC)(=O)C.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>[NH2:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([F:23])([F:24])[F:22])=[C:15]([F:14])[CH:16]=2)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(C(F)(F)F)c(F)c2)cc(N)c1Cl
Yield: 57.4 %

Procedure:
Methyl 4-amino-3,6-dichloropicolinate (630 mg, 2.85 mmol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.06 g, 3.65 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II) chloride (209 mg, 0.30 mmol, 0.1 equiv), and potassium fluoride (510 mg, 8.8 mmol, 3 equiv) in acetonitrile/water (8 mL, 3:1) was capped in a 25-mL vial on a Biotage Initiator™ microwave reactor for 20 min at 115° C., with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude compound was loaded onto a Celite™ cartridge and dried in vacuum oven. Purification by reverse-phase flash chromatography (0-60, 60, 60-100% acetonitrile/water) afforded the title compound as a white solid (0.57 g, 57%).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:58]([NH:65][CH2:66][CH:67]1[CH2:70][CH2:69][NH:68]1)([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>CN(C=O)C.CC(=O)OCC>[C:61]([O:60][C:58](=[O:59])[NH:65][CH2:66][CH:67]1[CH2:70][CH2:69][N:68]1[C:7]([C:2]1[C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])([CH3:64])([CH3:62])[CH3:63]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN1C(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
To a mixture of 2-biphenylcarboxylic acid (107 mg), PyBOP (280 mg), DIEA (0.215 mL) in dry DMF (0.5 mL), was added a solution of 2-(N-Boc-aminomethyl)azetidine (100 mg) in dry DMF (0.5 mL). The resulting reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with EA, washed with water. The aqueous phase was extracted once again with EA, the combined organic extracts were dried (MgSO4), filtered and concentrated to yield the crude product as light brown oil. FC (EA) gave 140 mg (71%) of the title compound as a light yellow oil.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([CH2:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=4[O:29][CH3:30])[C:14]=3[CH:31]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([CH2:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=4[O:29][CH3:30])[C:14]=3[CH:31]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cn1cnc2ccc(NC(=O)OC3CCCC3)cc21
Reaction time: 4 h
Yield: 78 %

Procedure:
A stirred solution of methyl 4-[6-(cyclopentyloxycarbonyl)aminobenzimidazol-1-ylmethyl]-3methoxybenzoate in 1:1 v/v tetrahydrofuran:methanol (7 ml.) was treated with water (1.4 ml.) and lithium hydroxide monohydrate (0.3 g.). Stirring was continued at ambient temperature for 4 hours. The solvent was then evaporated. The resultant residue was dissolved in water. The solution obtained was acidified with 10% v/v hydrochloric acid. The resultant precipitate was collected by filtration to give the title compound (0.43 g., 78%). An analytical sample was obtained as a white powder by recrystallization from aqueous ethanol; m.p. 241°-242° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]=[C:3]1[CH3:9].[CH3:10][I:11]>ClCCl>[I-:11].[CH3:1][N+:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]([CH3:10])[C:3]=1[CH3:9]
Reactant: CI
Reactant: Cc1nc(C)n(C)c1C
Solvent: ClCCl
Product: Cc1c(C)[n+](C)c(C)n1C
Product: [I-]

Procedure:
1,2,4,5-tetramethylimidazole was treated with 3 to 4 molar equivalents of methyl iodide in dichloromethane solvent and refluxed for three hours. The solvent was then removed by vacuum to yield 1,2,3,4,5-pentamethylimidazolium iodide which was used in the
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]2=[O:21])[CH2:3]1
Reactant: CC1CC(=O)c2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC1CC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 130 °C
Yield: 13.4 %

Procedure:
A mixture of 0.5 g of 3-methyl-1-indanone, 1.37 g oxindole and 5 ml piperidine in 3 ml of dimethylforamide was heated in a sealed tube at 130° C. overnight to yield a reddish-brown suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. Chromatography afforded 120 mg of 3-(3-methylindan-1-ylidene)-1,3-dihydroindol-2-one as an orange solid.