Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:26])[CH:6]=[C:7]([CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]([Cl:38])=[CH:35][CH2:36]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:26][CH2:36][CH:35]=[C:34]([Cl:38])[Cl:33])[CH:6]=[C:7]([CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCc1cc(O)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a mixture of 0.6 g of 3-ethyl-4-[3-(4-trifluoromethoxyphenoxy)propyloxy]-5-methylphenol, 0.22 g of potassium carbonate and 10 ml of N,N-dimethylformamide was added dropwise a solution of 0.31 g of 1,1,3-trichloro-1-propene dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.5 g of 3-ethyl-4-[3-(4-trifluoromethoxyphenoxy)propyloxy]-5-methyl-1-(3,3-dichloro-2-propenyloxy)benzene (71% yield), nD23.5 1.5150.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C1COCC1.[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(CCCO)cc2)nc1C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
The product of step (vi) (14.5 g, 31.3 mmol) was added to a plastic vessel and THF (150 mL) added. HF (30 mL) was added carefully to the solution and the solution stirred at room temperature for 3 hours. The mixture was poured to 600 mL of water and 5 N—NaOH added to basify the solution to pH=10-11. The solution was extracted with EtOAc and washed with water (×3). The combined EtOAc extract was dried over MgSO4, filtered and concentrated in vacuo, which afforded the subtitle compound (vii) as a yellow solid (10 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:24]([C:20]1[N:21]=[CH:22][N:23]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:19]=1)(=[O:25])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ncn1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
0.20 g (0.67 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.15 g (0.33 mmol) (6-chloro-pyrimidin-4-yl)-phenyl-methanone and 0.20 mL (1.1 mmol) DIPEA in 3 mL DMF were heated to 80° C. for 1 h. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13](O)[CH3:14]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(F)cc(F)c1

Procedure:
5 g of 3,5-difluorophenylacetic acid are dissolved in 50 ml of ethanol and 3 ml of concentrated H2SO4, and the mixture is heated at reflux for two hours. The mixture is evaporated to dryness, neutralization is then carried out with a saturated K2CO3 solution, extraction is then carried out with AcOEt and the organic phase is evaporated to produce 5.0 g of the expected compound in the form of a colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:13])=[N:8]2.[H][H]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:13])[NH:8]2
Reactant: COc1cccc2nc(C)ccc12
Reactant: [H][H]
Solvent: CO
Product: COc1cccc2c1CC[C@H](C)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
A 30-mL glass-lined stainless steel reactor with a magnetic stirring bar was charged with 5-methoxy-2-methylquinoline (4.0 g, 23.1 mmol), Ru(OTf)(η6-hexamethylbenzene)((S,S)-TsDPEN)([N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-hexamethylbenzene](1,1,1-trifluoromethanesulfonato-κO)-ruthenium, prepared according to the procedure in J. Am. Chem. Soc. 2011, 133, 9878-9891) (0.100 g, 0.13 mmol) and methanol (10 mL). The reactor was closed and hydrogen gas was initially introduced in at a pressure of 50 atm, before being reduced to 1 atm. After this procedure was repeated three times, the reactor was pressurized with hydrogen to 50 atm. The resulting mixture was stirred under this hydrogen pressure for 24 h at room temperature. After carefully releasing the hydrogen, the reaction mixture was concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 0-20% ethyl acetate/petroleum ether) to afford (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (4.0 g, 98%, >99% ee) as yellow oil. MS (ES, m/z): 178 [M+H]+
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH2:1]([N:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=1)[C:9]1[C:10]([CH3:16])=[C:11]([NH:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CN(Cc2ccccc2)c2cccc(N)c2C)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CN(Cc2ccccc2)c2cccc(NS(C)(=O)=O)c2C)cc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
The crude product from Example 6C in pyridine (8.8 mL) was treated with methanesulfonyl chloride (0.28 mL, 3.60 mmoles) at 0° C. The reaction mixture turned from clear and colorless to yellow. After 30 minutes, the mixture was quenched with water (5.0 mL) and was concentrated under reduced pressure. The residue was dissolved in diethyl ether (200 mL), washed with water (2×100 mL), brine (100 mL), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 4:1→1:1 hexanes:ethyl acetate) to provide the title compound as a yellow solid (1.33 g, 83%). A small portion of the residue (0.1 g) was repurified by preparative HPLC (CH3CN:0.1% TFA in H2O) on a YMC ODS Guardpak column. 1H NMR (300 MHz, CDCl3) δ7.92 (d, J=6.8 Hz, 2H), 7.21 (m, 8H), 7.11 (t, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.11 (s, 1H), 4.12 (s, 2H), 4.05 (s, 2H), 3.90 (s, 3H), 2.95 (s, 3H), 2.34 (s, 3H); MS (APCI+) m/z 439 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[CH3:26].N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[CH3:26])(=[O:5])=[O:4]
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride was dropwise added, under ice-cooling, to a mixture of 4-hydroxy-3,5-dimethylbenzonitrile, pyridine and dichloromethane, followed by stirring at room temperature for 2 hours to obtain 4-cyano-2,6-dimethylphenyl trifluoromethanesulfonate. In an atmosphere of nitrogen, a mixture of 4-cyano-2,6-dimethylphenyl trifluoromethanesulfonate, (3-formylphenyl)boronic acid, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred at room temperature for 6 hours to obtain 3′-formyl-2,6-dimethylbiphenyl-4-carbonitrile.
Reaction SMILES: [CH2:1]([NH:9][NH2:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:12]([CH2:18][C:19](=O)[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:20][C:19]1[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1
Reactant: NNCCc1ccccc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Product: CCOC(=O)c1cc(C)n(CCc2ccccc2)n1

Procedure:
The title compound was prepared from phenethyl hydrazine (3.92 g, 0.029M) (obtained by the method of J. H. Biel U.S. Pat. No. 3,000,903) and ethyl 2,4-dioxovalerate (4.55 g, 0.029M) as described in Example 1, Preparation 1 as a yellow oil (3.84 g, 52%); νmax(CH2Cl2) 1720 cm−1; δH(CDCl3) 1.40 (3H, t, J7 Hz), 1.90 (3H, s), 3.14 (2H, t, J7 Hz), 4.30 (2H, t, J7 Hz), 4.41 (2H, q, J7 Hz), 6.48 (1H, s), 6.97-7.09 (2H, m), and 7.20-7.37 (3H, m); E.I. m/e 258.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH3:13][C:14]([CH:17]=[O:18])([CH3:16])[CH3:15].[Cl-].[NH4+]>C(OCC)C>[CH3:13][C:14]([CH3:16])([CH3:15])[CH:17]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[OH:18]
Reactant: CC(C)(C)C=O
Reactant: Ic1cnccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)C(O)c1cnccn1
Temperature: 25 °C

Procedure:
A solution of 2-iodopyrazine (1.0 g, 4.85 mmol) in dry diethylether (10 ml) was added to a solution of n-butyl lithium (4.04 ml of 1.5M, 6.06 mmol) in dry diethylether (20 ml) at -50° C. over a period of 5 minutes under a nitrogen atmosphere. This was followed immediately by the addition of a solution of pivaldehyde (0.65 g, 7.58 mmol) in dry diethylether (10 ml). The reaction mixture was allowed to warm to room temperature over 4 hours and then poured into a mixture of ice and 10% ammonium chloride solution. The aqueous solution was extracted with diethylether (3×50 ml). The combined extracts were washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was taken up in diethylether and filtered through a bed of silica gel. The filtrate was concentrated under reduced pressure to give the product as a clear oil. (0.76 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)[CH3:14].C(Cl)Cl>C1COCC1.[Ni]>[CH3:14][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22])[CH2:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1]
Reactant: Cc1ccc2ccccc2c1CC(C)Oc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2ccccc2c1CC(C)Oc1ccccc1N

Procedure:
2-Methyl-1-[2-(2-nitro-phenoxy)-propyl]-naphthalene (1.51 g, 4.70 mmol) was shaken with Rainey nickel (0.5 g) in THF (50 mL) at 49.0 psi H2 for 5.4 hours. TLC analysis (silica, CH2Cl2) indicated complete consumption of starting material. The reaction mixture was filtered and concentrated to give 2-[1-methyl-2-(2-methyl-naphthalen-1-yl)-ethoxy]-phenylamine in quantitative yield. MS (APCI) m/z 292.1 (M+H).
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([NH:56][CH2:57][C:58]([O:60]C(C)(C)C)=[O:59])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:55])[CH2:29][CH2:30][CH:31]([CH:33]3[C:49]4([CH3:50])[CH:36]([CH:37]5[CH:46]([CH2:47][CH:48]4[OH:51])[C:45]4([CH3:52])[CH:40]([CH2:41][CH:42]([OH:53])[CH2:43][CH2:44]4)[CH2:39][CH:38]5[OH:54])[CH2:35][CH2:34]3)[CH3:32])=[CH:23][CH:22]=2)[CH2:14][CH2:13][N:12]([CH2:65][C:66]([O:68]C(C)(C)C)=[O:67])[CH2:11][CH2:10]1)=[O:7])(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:6]([CH2:8][N:9]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([NH:56][CH2:57][C:58]([OH:60])=[O:59])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:55])[CH2:29][CH2:30][CH:31]([CH:33]3[C:49]4([CH3:50])[CH:36]([CH:37]5[CH:46]([CH2:47][CH:48]4[OH:51])[C:45]4([CH3:52])[CH:40]([CH2:41][CH:42]([OH:53])[CH2:43][CH2:44]4)[CH2:39][CH:38]5[OH:54])[CH2:35][CH2:34]3)[CH3:32])=[CH:23][CH:22]=2)[CH2:14][CH2:13][N:12]([CH2:65][C:66]([OH:68])=[O:67])[CH2:11][CH2:10]1)([OH:7])=[O:5]
Reactant: CC(CCC(=O)Nc1ccc(CC(CN2CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC2)NCC(=O)OC(C)(C)C)cc1)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(CCC(=O)Nc1ccc(CC(CN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)NCC(=O)O)cc1)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.8 %

Procedure:
To a solution of Compound 3 (20 mg, 0.02 mmol) in a ice-bath was added 4M HCl in 1,4-dioxane (5 mL). After the addition, the reaction mixture was gradually increased to room temperature and stirred for 24 h. To this solution, ether (30 mL) was added and continuously stirred for 30 min. The resulting mixture was placed in the freezer for 2 h. Solid residue was quickly filtered, washed with ethyl ether (5 mL), immediately dissolved in H2O and CH3OH, and lypophilized to provide pure Compound 4 as a light brownish solid (19 mg, 97%). 1H NMR (CD3OD) 0.71 (s, 3H), 0.58-0.95 (m, 6H), 0.96-1.17 (m, 5H), 1.21-2.05 (m, 26H), 2.10-2.52 (m, 5H), 2.55-3.09 (m, 4H), 3.15-4.12 (m, 10H), 7.27 (d, 2H), 7.56 (d, 2H). HRMS (Positive ion FAB) Calcd for C45H72N5O10 [M+H]+ m/z 842.5279. Found: [M+H]+ m/z 842.5265.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10](Cl)=[O:11].O>CN(C=O)C>[CH3:1][N:2]1[CH2:13][CH:9]([C:8]([F:15])([F:14])[F:7])[C:10](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: C=C(C(=O)Cl)C(F)(F)F
Reactant: CNC(=O)NC
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of 1,3-dimethylurea (423 mg; 4.8 mmoles) in DMF (5 ml) was cooled to 0° C., and α-trifluoromethylacryloyl chloride (792 mg; 5.0 mmoles) was added dropwise. The mixture was stirred at room temperature for 1 hour. Then, water (20 ml) was added, and the mixture was extracted with methylene chloride (20 ml×1, 10 ml×2). The combined extracts were dried over anhhdrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel (chloroform) to give 508 mg (yield: 50%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil (OF-1).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: NCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCCCN(Cc1cccc(Cl)c1)c1ccccn1
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Sodium hydride (1.32 g) was dissolved in DMSO (25 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(3-aminopropylamino)pyridine (7.56 g) in DMSO (20 ml) added at room temperature. 3-Chlorobenzyl chloride (8.86 g) in DMSO (15 ml) was added dropwise maintaining the temperature at 20°-25° C. After a further 1 hour, water was added (200 ml) and the mixture extracted with ether. The ether extracts were washed with 2N hydrochloric acid and the aqueous layer adjusted to pH 3.5. After extracting with chloroform the pH was raised to 14 and extracted with ether. After drying (K2CO3), the final ether extracts were stripped to give 2-[N-(3-aminopropyl)-N-(3-chlorobenzyl) amino]pyridine (8.34 g) as an oil which was used without further purification. (ii) 2-[N-(3-aminopropyl)-N-(3-chlorobenzyl)amino]pyridine (1.65 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.3 g) were heated together under reflux in pyridine (15 ml) for 20 hr. On cooling, the mixture was stripped, the residue triturated with wet ether and recrystallised twice from ethanol/water to give 2-[3-[N-(3-chlorobenzyl)-N-pyrid-2-ylamino]propylamino]-5-(6-methylpyrid-3-ylmethyl) pyrimid-4-one 0.6H2O, 1.29 g (53%) mp 100°-104° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23]([O:11][C:10](=[O:12])[CH:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:20][CH:19]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:22]2
Reactant: O=C(O)C(NCc1ccc(F)cc1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
A mixture of (4-fluoro-benzylamino)-phenyl-acetic acid hydrochloride (233 mg, 0.79 mmol), (R)-quinuclidin-3-ol (200 mg, 1.57 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (596 mg, 1.57 mmol), TEA (0.22 mL, 1.57 mmol) and HOBT (241 mg, 1.57 mmol) in acetonitrile (10 mL) is stirred at RT for 48 hours. THF is removed under vacuum and the crude is partitioned between EtOAc and water. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The crude is purified by preparative HPLC. The combined fractions are dried and partitioned between EtOAc and 2M K2CO3. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness to achieve the title compound as colorless oil (61 mg, 21% yield, mixture of diastereoisomers).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[OH-].[K+].[CH3:18][O:19][CH2:20][CH2:21]Br>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:13])[F:14])=[C:6]2[C:10]=1[N:9]([CH2:21][CH2:20][O:19][CH3:18])[CH:8]=[CH:7]2
Reactant: Fc1ccc(OC(F)(F)F)c2cc[nH]c12
Reactant: COCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCn1ccc2c(OC(F)(F)F)ccc(F)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
A mixture of 5 (16 g, 72.8 mmol) and powder KOH (20.4 g, 364.2 mmol) in DMSO (150 mL) is stirred at rt for 10 min. 2-Methoxyethyl bromide (10.3 mL, 109.2 mmol) is added. This mixture is stirred at rt overnight. LC/MS indicates the reaction is completed. The mixture is partitioned between H2O and Et2O. The two layers are separated, and the aqueous layer is extracted with Et2O (2×). The combined organic layers are washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc (100/0 to 50/50) as eluant to give 19.3 g (95%) of 6 as a yellow liquid. 1H NMR (CDCl3) δ 7.15 (d, J=2.1 Hz, 1H), 6.90-6.75 (m, 2H), 6.56 (t, J=2.5 Hz, 1H), 3.72 (t, J=5.2 Hz, 2H), 3.72 (t, J=5.2 Hz, 2H), 3.31 (s, 3H); 19F NMR (CDCl3) δ −57.54 (s, 3F), −137.00 (d, J=11.3 Hz, 1F); MS 278 (M+1, 100%).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:22]1([C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]1=[O:31])[CH2:21]2)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH2:1]([N:8]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:22]1([C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]1=[O:31])[CH2:21]2)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)N(CC#Cc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)N(CCCc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21)Cc1ccccc1
Reaction time: 20 h

Procedure:
To a nitrogen purged solution of N-Benzyl-2,2-dimethyl-N-[3-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)prop-2-yn-1-yl]propanamide (42 mg, 0.91 mmol, Example 1) in MeOH (4 mL) was added 10% Pd/C (19 mg). The nitrogen atmosphere was exchanged for a hydrogen atmosphere using a hydrogen balloon, and then a fresh hydrogen balloon was attached. After 1 hour a mixture of alkene/alkane was observed. Allow reaction to stir for 20 hours under an atmosphere of hydrogen. The hydrogen atmosphere was then exchanged for a nitrogen atmosphere, and the mixture was filtered through celite, and washed with additional MeOH. The combined organics were concentrated in vacuo to yield a residue. The residue was then applied to a silica gel column for purification, eluting with a gradient of 1-7% MeOH in DCM to give the title compound. MS: m/z=468 (M+1). Human CGRP receptor binding Ki=45 nM. HRMS: m/z=468.2632; calculated m/z=468.2642 for C30H34N3O2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(C(C)C)nc2)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(C(C)C)nc1)c1ccc(C(C)C)cc1)CCC2
Yield: 17.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and (4-isopropylphenyl)[(6-isopropylpyridin-3-yl)methyl]amine (0.46 g) as starting materials, N-(4-isopropylphenyl)-N-[(6-isopropylpyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)=O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1.O>C1COCC1>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)=[CH:9][C:10]#[N:11])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: COc1cccc(C(=O)c2ccc3c(c2)OCCO3)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (2.1 mL, 13.5 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.5 mL, 13.5 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-methoxy-phenyl)-methanone (2.0 g crude, 6.7 mmol) in THF (15 mL) and refluxed for 30 min. The reaction mixture was poured into water (50 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3-methoxy-phenyl)-acrylonitrile as an off-white solid (1.53 g, 77% yield): mp, 64-66° C.; 1H NMR (DMSO-d6) δ 3.77 and 3.78 (2s, 3H, OCH3), 4.24-4.36 (m, 4H, CH2CH2), 6.19 and 6.24 (2s, 1H, CH), 6.77-7.09 (m, 6H, Ar), 7.33-7.36 (m, 1H, Ar); 13C NMR (DMSO-d6) δ 55.2, 55.2, 64.0, 64.0, 64.2, 64.3, 94.3, 95.2, 113.7, 114.6, 114.9, 115.8, 116.7, 117.1, 117.2, 117.9, 118.3, 120.9, 121.2, 121.7, 122.5, 129.7, 129.8, 129.8, 130.6, 138.5, 139.7, 143.1, 143.3, 144.8, 145.6, 159.1, 159.2, 160.8, 160.9. Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.48; H, 4.84; N, 4.64.