Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@H:6]([NH:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]1[N:28](CCC#N)[N:27]=[N:26][N:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@H:6]([NH:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]1[NH:25][N:26]=[N:27][N:28]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of (R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-butyric acid ethyl ester (137 mg, 0.297 mmol) in DCM (8 mL) at room temperature is added DBU (1.507 mL, 10.00 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction is extracted with DCM. The combined organic layer is washed with saturated NH4Cl, brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced. The obtained residue is purified by flash chromatography (silica gel, 2% to 10% EtOH/DCM) to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid ethyl ester (37 mg). To the obtained ester in EtOH (2 mL) at room temperature is added aqueous 1M NaOH (1 mL, 1.0 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction is added 1 mL of aqueous 1M HCl to pH=4, and the mixture is purified by reverse phase HPLC [30% to 60% acetonitrile-H2O (0.1% TFA)] to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid. HPLC retention time=1.24 minutes (condition C); MS (m+1)=380; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (dd, J=6.7, 2.1 Hz, 2 H), 2.53 (t, J=7.6 Hz, 2 H), 2.69-2.82 (m, 2 H), 3.02 (t, J=7.7 Hz, 2 H), 4.17-4.29 (m, 1 H), 7.22 (d, J=8.3 Hz, 2 H), 7.34 (tt, J=7.3, 1.3 Hz, 1 H), 7.42-7.48 (m, 2 H), 7.57 (d, J=8.3 Hz, 2 H), 7.64 (dd, J=8.2, 1.1 Hz, 2 H), 8.00 (d, J=8.1 Hz, 1 H), 12.21 (br. s., 1 H), 15.92 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].[OH-].[Na+].[O-:14][C:15]#[N:16].[Na+].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:16][C:15](=[O:14])[NH:11]2
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(Cl)cccc2[nH]1
Reaction time: 9 h
Yield: 72.2 %

Procedure:
To a solution of 6-chloroanthranilic acid (1.72 g, 10 mmol) and NaOH (0.40 g, 10 mmol) in water (15 mL) was added sodium cyanate (0.72 g, 11 mmol), followed by acetic acid (0.66 g, 11 mmol). The solution was stirred for 9 h, and then acidified with conc. HCl. The precipitate was filtered off and washed with water. The wet solid was added to a solution of NaOH (8.0 g, 200 mmol) in water (60 mL) and stirred for 20 h. The precipitate was filtered off and suspended in water (80 mL), then heated to boiling and acidified with 50% H2SO4. The cooled mixture was filtered, the solid washed well with water and dried to give 5-chloroquinazolin-2,4-dione (1.42 g, 72%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1>>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH2:11])[CH:3]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Nc1cc(Cl)n2nccc2n1
Product: Cc1ccc(-c2cc(N)nc3ccnn23)cc1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (1E) and p-tolylboronic acid were used as starting materials. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.44 (s, 3H), 4.82 (s, 2H), 6.16 (s, 1H), 6.20 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.91 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cu][C:2]#[N:3].I[C:5]1[CH:10]=[C:9]([C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14]2)=[O:12])[CH:8]=[CH:7][C:6]=1[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1>CS(C)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]2[CH2:16][CH2:17][N:13]([C:11]([C:9]3[CH:10]=[C:5]([C:2]#[N:3])[C:6]([C:24]4[CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=4)=[CH:7][CH:8]=3)=[O:12])[CH2:14]2)[CH:19]=1
Reactant: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(I)c1)N1CCC(c2cccnc2)C1
Reactant: N#C[Cu]
Solvent: CS(C)=O
Product: N#Cc1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C

Procedure:
Copper(I) cyanide (42.9 mg, 0.479 mmol) was added to a stirred solution of 4b (200 mg, 0.368 mmol) in DMSO (4.00 mL), and the resulting mixture was heated to 180° C. for 12 h. The reaction mixture was cooled to rt, quenched with satd. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The resulting crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 6a. m/z (ES) 490 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])=[C:15]([C:26]#[CH:27])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.[H][H]>O1CCOCC1.O.[Pt]>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[O:20])=[C:15]([CH2:26][CH3:27])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: C#Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: [Pt]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 99 %

Procedure:
60 mg (0.143 mmol) of N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-ethynyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is dissolved in 6.0 mL dioxane/water (1:1), combined with 8.0 mg platinum/activated charcoal and hydrogenated for 7 hours with hydrogen (3 bar). Then the catalyst is filtered off and the solvent is distilled off. Yield: 99%; Rf value: 0.15 (Reversed-phase-8; methanol/5%-NaCl solution=3:2); C23H25ClN4O2 (424.93); mass spectrum: (M−H)-=423/425 (chlorine isotope) and (M+H)+=425/427 (chlorine isotope).
Reaction SMILES: N1CCCCC1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].[I:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[NH:20][N:19]=1>CCO>[I:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:7][C:8]3=[O:16])[CH:25]=2)[NH:20][N:19]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1ccc2[nH]nc(I)c2c1
Temperature: 75 °C
Reaction time: 14 h
Yield: 63.1 %

Procedure:
Piperidine (0.01 mL, 0.1 mmol) was added to a suspension of oxindole (72 mg, 0.54 mmol) and 3-iodo-1H-indazole-5-carbaldehyde (146 mg, 0.54 mmol) in EtOH (10 mL). On heating to 75° C., the suspended solid dissolved, and a new precipitate formed. Heating was continued at 75° C. for 14 hrs. After the mixture was cooled to room temperature, suction filtration and rinsing with EtOH (4×2 mL) gave 3-((3-iodo-1H-indazol-5-yl)methylene)indolin-2-one (yellow solid, 131.9 mg, 63%). 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s, 1H), 10.61 (br. s, 1H), 7.84 (s, 1H), 7.77 (m, 2H), 7.69 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.23 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.84 (m, 1H); MS ESI 388.0 [M+H]+, calcd for [C16H10IN3O+H]+ 388.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[I:22]I.[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O>[F:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[O:8][C:5]1[CH:4]=[CH:3][C:2]([I:22])=[CH:7][N:6]=1
Reactant: II
Reactant: Fc1ccc(Oc2ccc(Br)cn2)cc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2ccc(I)cn2)cc1F
Temperature: 20 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 5-bromo-2-(3,4-difluorophenoxy)pyridine (19 g, 66.4 mmol) in tetrahydrofuran (THF) (200 mL) was added isopropylmagnesium chloride (66.4 mL, 66.4 mmol). The reaction mixture was stirred at 20° C. for 2 hr, and then I2 (16.86 g, 66.4 mmol) was added, The reaction mixture was stirred at 20° C. for another 4 hr, then saturated aqueous NH4Cl solution (200 ml) and EtOAc (200 ml) were added, the organic layer was separated, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with Hex/EtOAc (20:1). The collected fractions provided 2-(3,4-difluorophenoxy)-5-iodopyridine (22 g, 61.7%).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].O>C(Cl)(Cl)(Cl)Cl>[C:18]([C:9]1[CH:10]=[CH:11][C:6]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:7][CH:8]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(C2CCNC2)cc1
Reaction time: 0.25 h
Yield: 33 %

Procedure:
98 g (1 mole) of concentrated sulfuric acid were added dropwise to 29.4 g (0.2 mole) of 3-phenylpyrrolidine in 400 ml of carbon tetrachloride at 0°-5° C. After 15 minutes, 15.2 g (0.27 mole) of isobutylene were passed in gaseous form, the mixture was stirred for 1 hour at 0°-5° C. and hydrolysis was carried out with 400 ml of water at 20° C. The organic phase was separated off and the aqueous phase was extracted with twice 100 ml of dichloromethane. Working up of the organic phases gave 42 g of a crude product, which was fractionated under reduced pressure to give 13.4 g (33%) of a colorless oil of boiling point 84°-87° C./0.5 mbar.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:11][C:10]=2[CH3:22])=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=2[CH3:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)O)ccc1-c1ccc(C#N)cc1
Reaction time: 1 h

Procedure:
(Step 2) To a solution of the preceding ester (3.0 g, 10.2 mmol) in methylene chloride (75 mL) at 0° C. was added TFA (75 mL) dropwise over 10 min. The ice bath was removed and stirring continued for 1 h at rt. The mixture was concentrated on a rotary evaporator and then diluted with toluene and reconcentrated to afford 4′-cyano-2-methyl-1,1′-biphenyl-4-carboxylic acid. ESI-MS m/e 228.1 (M+1).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[CH2:32][CH2:33][C@@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([CH3:14])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[C@H:29]([OH:34])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f43) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N+:3]=1[O-].ClC1N=C(C[O:19][C:20](=[O:22])[CH3:21])C=CC=1>>[C:20]([O:22][CH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:19])[CH3:21]
Reactant: COc1cc[n+]([O-])c(C)c1
Reactant: CC(=O)OCc1cccc(Cl)n1
Product: COc1ccnc(COC(C)=O)c1

Procedure:
Starting with 2-methyl-4-methoxypyridine-1-oxide (2.1 g) in the procedure of Part (ii) afforded 2.5 g of 2-acetoxymethyl-4-methoxypyridine which was contaminated with about 25% of 5-acetoxy-2-methyl-4-methoxypyridine. This mixture was dissolved in methanol (10 ml) containing 1.118 g (20.7 mmole) sodium methoxide and stirred at reflux for one hour. The methanol was evaporated in vacuo, the residue diluted with water, neutralized with dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give 853 mg (41%) 2-hydroxymethyl-4-methoxypyridine. 1H--NMR(CDCl3)ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (bs, 1H), 6.7 (dd, 1H), 6.95 (d, 1H), 8.3 (d, 1H).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Yield: 93.2 %

Procedure:
Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate (0.11 g, 0.14 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1 N NaOH (0.5 mL) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and extracted with ethyl acetate. The extract was dried over sodium sulfate, and evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.10 g of 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoic acid as a white solid; mp 117-119° C.; HRMS: calcd for C39H32Cl3FN2O5S, 764.1082; found (ESI+), 787.09794
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH2:8]2)[CH2:4][CH2:3]1.CCN(CC)CC.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32](Cl)=[O:33])=[CH:26][CH:25]=1>C(Cl)Cl>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([C:32]([O:31][CH2:30][C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)=[O:33])[CH2:3][CH2:4]2)[CH2:8]1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution spiro[indene-1,4′-piperidin]-3(2H)-one hydrochloride (5.0 g, 24.84 mmol) and Et3N (7.54 g, 74.53 mol) in CH2Cl2 (50 mL) was added drop-wise Cbz-Cl (4.66 g, 27.33 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The precipitate was filtered, washed with Et2O and dried to furnish benzyl 3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (6.1 g, yield 99%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[NH2:1][C:2]1[S:3][C:4]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1
Reactant: CC(C)(C)c1nc(N)sc1Br
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1nc(N)sc1N1CCCCC1
Yield: 79.3 %

Procedure:
A mixture of 2-amino-5-bromo-4-[(1,1-dimethyl)ethyl]thiazole (0.10 g, 0.42 mmol), piperidine (0.1 mL), potassium carbonate (0.20 g) and acetonitrile (4 mL) was refluxed for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (80.7 mg, 79.3%) as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12](Cl)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=1[CH3:23].CCN(CC)CC>ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][C:12]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:11][CH2:10]2)=[O:13])[CH:19]=[CH:18][C:17]=1[CH3:23]
Reactant: COc1ccc(C2(C(=O)Cl)CC2)cc1
Reactant: Cc1ccc(N)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(Cl)n3)CC2)cc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 1-(4-methoxyphenyl)cyclopropanecarbonyl chloride (21.1 mmol) in anhydrous dichloromethane (20 mL) was slowly added to a cooled solution (0° C.) of 6-chloro-5-methylpyridin-2-amine (21.2 mmol) in dichloromethane (50 mL) and Et3N (14.1 mL, 101 mmol). The reaction mixture was stirred at room temperature for 2Hours. The resulting mixture was diluted with dichloromethane and washed with water (1×30 mL), 1N NaOH (2×30 mL), 1N HCl (1×30 mL), saturated aqueous NaHCO3 (1×30 mL) and brine (1×30 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield N-(6-chloro-5-methylpyridin-2-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (4.0 g, 63%) as a white solid. ESI-MS m/z calc. 316.1, found 317.3 (M+1)+. Retention time 1.98 minutes. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 3.88 (s, 3H), 2.31 (s, 3H), 1.72-1.69 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[C:5]([O:9][C:10]([C:12]1[CH:28]=[C:27]([OH:29])[C:15]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:5]([O:9][C:10]([C:12]1[CH:28]=[C:27]([O:29][CH:2]([CH3:4])[CH3:3])[C:15]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(COc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(COc1ccccc1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-Iodopropane (174 mg, 1.02 mmol)) was added to a mixture of 4-hydroxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214b) (350 mg, 1.02 mmol) and K2CO3 (141 mg, 1.02 mmol) in DMF (5 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with H2O (2×70 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 5% EtOAc in hexanes to give a white solid (182 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=1.26 Hz, 1 H) 7.22-7.26 (m, 1 H) 7.13 (s, 1 H) 7.07 (s, 1 H) 6.91-7.00 (m, 3 H) 6.85 (d, J=7.58 Hz, 1 H) 5.17-5.25 (m, 1 H) 4.59-4.68 (m, 1 H) 4.07-4.17 (m, 1 H) 3.34 (dd, J=16.55, 9.47 Hz, 1 H) 3.09 (dd, J=16.55, 6.95 Hz, 1 H) 1.58 (s, 9 H) 1.35 (d, J=6.06 Hz, 6 H); LCMS for C23H28O5 m/z 385.20 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:35])[NH:15][CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:20]1([CH2:19][CH2:18][CH2:17][CH:16]([NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:35])[CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
4-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (3) (0.77 g; 1.61 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (10 mL) and water (100 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (200 mL) then extracted with methylene chloride (3×100 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.58 g) as an oil.
Reaction SMILES: [CH2:1]([N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:18]([NH2:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:11]1[C:12](=[O:17])[CH2:13][CH:14]([NH:28][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN1C(=O)C=CC1=O
Reactant: CCCCCCCCCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC1CC(=O)N(CCCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-decyl maleimide (0.01 M) prepared as described in Example 11 above, decylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH:12]1[C:20]2[N:15]([CH:16]=[CH:17][C:18](=O)[CH:19]=2)[CH2:14][CH:13]=1>O>[CH2:12]1[CH:20]2[N:15]([CH2:16][CH:17]=[C:18]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:3][CH:4]=3)[CH2:19]2)[CH2:14][CH2:13]1
Reactant: O=c1ccn2c(c1)C=CC2
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C1=C(c2c[nH]c3ccccc23)CC2CCCN2C1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
Potassium hydroxide (10% in methanol, 15 ml, 26.8 mmol), 1H-indole (1.5 g, 13 mmol), and 7-indolizinone (1.39 g, 10 mmol) were combined and heated to reflux for 15 hours. The mixture was diluted with water and the precipitate was filtered. The brown filter cake was triturated with hot methanol, cooled to room temperature, and the solid collected to give 1.99 g of desired product. (84%).