Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[C:3]=1[O:23][CH3:24].[OH-].[Na+].[CH:27](O)=O>C=O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:27])[CH2:8][CH:7]([C:13]3[CH:14]=[CH:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=3)[C:6]=2[CH:5]=[C:4]([O:21][CH3:22])[C:3]=1[O:23][CH3:24]
Reactant: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccc(SC)cc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(c(Cl)c1OC)CCN(C)CC2c1ccc(SC)cc1

Procedure:
A solution of 4 g of 6-chloro-7,8-dimethoxy-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml of formic acid and 10 ml of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give 6-chloro-7,8-dimethoxy-3-methyl-1-(p-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[C:26]([NH2:27])=[CH:25][C:24]([CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:23]1)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[CH:7][C:2]([NH:27][C:26]2[N:22]([CH2:20][CH3:21])[N:23]=[C:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: CCn1nc(CCN2CCCC2)cc1N
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCn1nc(CCN2CCCC2)cc1Nc1cc(Nc2ccccc2C(=O)NC)c(Cl)cn1
Temperature: 170 °C
Reaction time: 0.67 h
Yield: 39.2 %

Procedure:
To a 5-mL microwave tube were added 2-[(2,5-dichloro-4-pyridinyl)amino]-N-methylbenzamide (100 mg, 0.338 mmol), 1-ethyl-3-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-5-amine (70.3 mg, 0.338 mmol), cesium carbonate (330 mg, 1.013 mmol), and 1,4-dioxane (2 mL), and the mixture was degassed by bubbling nitrogen through for 15 min. Palladium (II) acetate (3.79 mg, 0.017 mmol) and BINAP (21.03 mg, 0.034 mmol) were added, and the reaction mixture was heated at 170° C. with stirring under microwave conditions for 40 min. The reaction mixture was filtered and concentrated. The residue was purified by using RP-HPLC under basic conditions (Gemini 5u C18(2) 110A, AXI. 50×30.00 mm 5 micron: 7.3-minute run, 47 mL/min, 40% ACN/H2O, 0.1% NH4OH to 90% ACN/H2O, 0.1% NH4OH with UV detection at 254 nm) to give the title compound (62 mg). MS: (M+H)+=468.1. 1H NMR (400 MHz, DMSO-d6) ppm 1.21 (t, J=7.2 Hz, 3 H), 1.67 (m, 4H), 2.45 (m, 4), 2.60 (m, 4H), 2.77 (d, J=4.0 Hz, 3H), 3.89 (q, J=7.2 Hz, 2H), 6.03 (s, 1H), 6.74 (s, 1H), 7.11 (m, 1H), 7.49 (m, 1H), 7.54 (m, 1H), 7.71 (d, J=7.2 Hz, 1H), 8.00 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:13][OH:14].F[C:16]1[C:21]2[N:22]=[C:23]([C:25]3[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH2:13][O:14][C:16]1[C:21]2[N:22]=[C:23]([C:25]3[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ncccc1-c1nc2c(F)cccc2o1
Reactant: COc1ccc(CO)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc3oc(-c4cccnc4N)nc23)c(OC)c1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Sodium hydride (1.08 g, 60% in mineral oil) was added to a stirred solution of (2,4-dimethoxyphenyl)methanol (4.54 g) dissolved in tetrahydrofuran (150 ml) over a period of 5 minutes at 0° C. After 30 minutes, 3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (1.547 g) was added and the mixture was heated to reflux for 16 hours. The THF was evaporated, water was added and the resultant solid was filtered and washed with water. The solid was then triturated with diethyl ether and dried with phosphorus pentoxide under reduced pressure to afford 3-[4-[(2,4-dimethoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]pyridin-2-amine (2.32 g) as a solid. NMR Spectrum: (CDCl3) 3.82 (s, 3H), 3.86 (s, 3H), 5.41 (s, 2H), 6.50 (dd, 1H), 6.51 (s, 1H), 6.75 (dd, 1H), 6.91 (d, 1H), 6.96 (bs, 2H), 7.17 (d, 1H), 7.24 (d, 1H), 7.41 (d, 1H), 8.20 (dd, 1H), 8.29 (dd, 1H); Mass spectrum: M+H+ 378
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].C(=O)=[O:12]>O>[C:8](=[O:9])([OH:12])[OH:10].[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: O=C=O
Agent: NCCCC[C@H](N)C(=O)O
Solvent: O
Product: O=C(O)O

Procedure:
146 g of lysine are dissolved in water and the solution is saturated with CO2 so as to obtain a 30% solution of lysine carbonate. Separately 226.6 g of 4-allyloxy-3-chlorophenylacetic acid are dissolved in 800 ml of isopropyl alcohol. The two solutions are joined by pouring the alcoholic solution into the aqueous solution with light stirring. Stirring is continued 5 hours at room temperature.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[N:5]=[CH:4][N:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3][CH:4]=[N:5][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: Cc1ccccc1-c1ncnc(Cl)c1C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1-c1ncnc(-c2ccccc2)c1C
Yield: 87 %

Procedure:
Next, into a recovery flask equipped with a reflux pipe were put 1.9 g of 4-chloro-5-methyl-6-(2-methylphenyl)pyrimidine obtained in Step 1, 1.7 g of phenylboronic acid, 1.1 g of sodium carbonate, 0.105 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 1 hour. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and was dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 9:1 and the obtained fraction was concentrated, so that 5-methyl-6-(2-methylphenyl)-4-phenylpyrimidine was obtained (a white solid, yield of 87%). A synthesis scheme (q-2) of Step 2 is shown below.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCN)([CH3:4])([CH3:3])[CH3:2].C(OC(COC(C[NH:37]CC(O)=O)=O)=O)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCN
Reactant: CC(C)(C)OC(=O)COC(=O)CNCC(=O)O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCN

Procedure:
15-Aminopentadecanoic acid tert-butyl ester was prepared in analogous fashion to 17-aminoheptadecanoic acid tert-butyl ester, and was coupled to (tert-butoxycarbonylmethoxycarbonylmethylamino) acetic acid in analogous fashion to the method described in Example 1, step 4.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][C:11]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.[N-:25]=[N+:26]=[N-:27].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][N:2]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[C:11]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]3[NH:27][N:26]=[N:25][N:22]=3)=[CH:23][CH:24]=1)[CH:10]=2
Reactant: Cn1c2c(c3cc(-c4ccc(OCC#N)cc4)ccc31)CCCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(-c4ccc(OCc5nnn[nH]5)cc4)ccc31)CCCC2

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenoxy]-acetonitrile (0.149 g, 0.471 mmol) was reacted with NaN3 (0.153 g, 2.355 mmol) and NH4Cl (0.126 g, 2.355 mmol) in DMF (5 ml) to give the product (0.060 g, 0.167 mmol, 35%) as a white solid, dec. 205-211° C. 1H NMR (DMSO-d6) δ 1.76-1.81 (m, 2H), 1.86-1.90 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.71 (t, J=5.8 Hz, 2H), 3.61 (s, 3H), 5.51 (s, 2H), 7.11 (d, J=8.7 Hz, 2H), 7.31 (dd, J=1.5, 8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.61 (d, J=8.7 Hz, 2H), 16.78 (broad s, 1H); IR (solid) 2930, 2850, 1520, 1480, and 1240 cm−1; [ESI(+)], m/z 360 (M+H)+; Anal. Calcd. for C21H21N5O: C, 70.18; H, 5.89; N, 19.48; Found: C, 69.94; H, 5.70; N, 19.67.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C([O-])(O)=O.[Na+]>O.C1COCC1>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:9]2[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:26][CH:25]=3)[C:8]2=[O:24])=[CH:15][CH:16]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(CN2CCCN(Cc3ccc(N)cc3)C2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CN2CCCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-tetrahydropyrimidin-2-one (L) (438 mg, 1.24 mmol) and triethylamine (0.22 mL, 1.6 mmol) in abs. THF (50 mL) there was added a solution of methanesulphonyl chloride (0.11 mL, 1.48 mmol) in 5 mL of abs. THF within a period of 15 min. The reaction mixture was stirred over a period of 48 h at RT, sat. NaHCO3 solution (20 mL) was added, and the mixture was stirred for 30 min. H2O (30 mL) was added, and the mixture was extracted with EtOAc (3×30 mL). The combined organic phases were washed with sat. NaCl solution (30 mL), dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by means of column chromatography (SiO2 (50 g) using cyclohexane/EtOAc 1:1 (500 mL) as eluent). The desired product N-{4-[3-(4-tert-butyl benzyl)-2-oxotetrahydropyrimidin-1-yl methyl]phenyl}methanesulfonamide (5) was obtained as a white solid (398 mg, 75% of theory) having a melting point of 132-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[Br:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Br:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C:14]([NH:13][C:4]2[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(OCCBr)cc1
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(OCCBr)cc1

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-(2-bromoethyloxy) benzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-[4-(2-bromoethyloxy)benzenesulfonyl]-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and further to obtain from 760 mg (1.50 mmol) of N-[4-(2-bromoethyloxy)benzenesulfonyl]-N'-(2-carboxyl-5-chlorophenyl)urea 320 mg of the above-identified compound (yield 46.4%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):3.82 (2H,t), 4.46 (2H,t), 7.12 (1H,s), 7.12-7.23 (3H,m), 7.85 (1H,d), 8.11 (2H,d), 11.59 (1H,s).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:31])[C@H:8]1[CH2:12][C@@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][N:9]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CN(C)C=O>[CH3:5][O:6][C:7](=[O:31])[C@H:8]1[CH2:12][C@H:11]([N:1]=[N+:2]=[N-:3])[CH2:10][N:9]1[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25]
Reactant: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Sodium azide (515 mg) was added to a stirred solution of N-tert-butoxycarbonyl-cis-4-(p-toluenesulfonyloxy)-D-proline methyl ester (B, 1.65 g) in N,N-dimethylformamide (10 mL)-water (2 mL). After stirring at 80-90° C. for 1 hr, the solvents were removed in vacuo. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (1.04 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(O)C>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[C:2]([OH:1])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1c(O)cccc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,6-dihydroxybenzoic acid (500 mg, 3.24 mmol) in ethanol (8 mL) is added NaOH (130 mg, 3.24 mmol). After the mixture is stirred at RT for 3 h, the solvent is removed under reduced pressure. The resulting sodium salt is dissolved in DMF (10 mL) then benzyl bromide (0.39 mL, 3.24 mmol) is added and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound as an oil.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:34]=[N:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[C:33]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)[CH:34]=[N:35][CH:36]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2cncc(N3CCOCC3)c2)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4cncc(N5CCOCC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]morpholine (from Small Molecules). LCMS calculated for C25H28N5O3 (M+H)+: m/z=446.2. Found 446.1.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:25]1[NH:26][CH2:27][CH2:28][N:29]=1>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:25]2[NH:29][CH2:28][CH2:27][N:26]=2)=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: CSC1=NCCN1
Agent: I
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc2c(CNC3=NCCN3)cccc2c1
Temperature: 150 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide were added to methylene chloride and the reaction mixture was heated to reflux until all of the solvent evaporates. The reaction mixture is heated to 150° C. and then cooled. The resulting mixture is basified by dropwise addition of aqueous NaOH solution, and then purified by preparative liquid chromatography to give (6-benzenesulfonyl-naphthalen-1-ylmethyl)-(4,5-dihydro-1H-imidazol-2-yl)-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].C([Li])CCC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>O1CCCC1.CCCCCC>[OH:23][CH:22]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6])[C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CNC(=O)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1cccc(C(O)c2ccc(F)cc2)c1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A solution of 3-bromo-N-methylbenzamide (3.48 g, 16.25 mmol) in dry tetrahydrofuran (100 ml) was cooled to −78° C. and treated dropwise over 10 min. with 13 ml (32.5 mmol) of a 2.5 M solution of n-butyllithium in hexane. After 15 min. at −78° C., a solution of 4-fluorobenzaldehyde (2.5 g, 20.1 mmol) in tetrahydrofuran (10 ml) was added dropwise over 10 min. and the resulting mixture was stirred for another 45 min at the same temperature. The temperature was then allowed to reach −20° C. and the mixture was quenched by the addition of saturated ammonium chloride. The reaction mixture was then extracted with ethyl acetate and the organic layer was washed with 0.1N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and crystallization of the residue from ethyl acetate gave 1.60 g (38%) of the title compound as a white solid: mp: 138-139° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.0 and 3.01 (3H, 2 s, NCH3), 5.88 (1H, s, CH), 6.19 (1H, broad, NH), 7.03 (2H, m, aromatics), 7.36 (2H, m, aromatics), 7.41 (1H, t, J=7.6 Hz, aromatic), 7.49 (1H, d, J=7.6 Hz, aromatic), 7.66 (1H, d, J=7.6 Hz, aromatic), 7.79 (1H, s, aromatic). Anal. Calcd for C15H14FNO2: C, 69.49; H, 5.44; N, 5.40. Found: C, 69.41; H, 5.41; N, 5.63.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:25][CH:22]2[CH2:23][CH2:24][O:19][CH2:20][CH2:21]2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)c1csc(NC(=O)[C@@H]2CCCN2CC2CCOCC2)n1
Reaction time: 0.62 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (4-tert-butyl-thiazol-2-yl)-amide; hydrochloride (0.310 g; 1.070 mmol) in 1,2-dichloroethane (2 mL) was added tetrahydro-pyran-4-carbaldehyde (0.244 g; 2.140 mmol), acetic acid (0.2 mL; 3.497 mmol), and sodium sulfate(5-10 equivalents). The mixture is stirred for 30-45 minutes before adding sodium triacetoxyborohydride (0.454 g; 2.140 mmol) and stirring overnight at room temperature. After this time, the mixture is filtered through a plug of silica/Celite® and concentrated in vacuo. Crude material is purified by preparative HPLC. Product fractions are pooled and concentrated in vacuo to afford title compound as an oil. ESI m/z 352 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:33]C1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:33])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 250.0 mg (0.522 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 249.0 mg (1.827 mmol) of zinc chloride, 24 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF, and 4-ethylphenyl lithium (prepared by adding 167.7 mg (1.54 ml, 2.62 mmol) of tert-butyllithium (1.7M solution in pentane) to a cold solution (-78° C.) of 244.0 mg (1.305 mmol) of 4-ethylbromobenzene in 2.0 ml of THF). 1H NMR (CDCl3): δ 7.99 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.4 Hz), 7.42-7.24 (7H, m), 5.99 (1H, t, J=4.7 Hz), 4.37 (2H, q, J=7.1 Hz), 2.71 (2H, q, J=7.6 Hz), 2.35 (2H, d, J=4.7 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:12][C:13]([O:16]C)=[CH:14][CH:15]=1.[Cl-].[NH+]1C=CC=CC=1.Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[N:12][C:11]=1[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: COc1ccc(F)c(-c2ccc(OC)nc2CC(C)(C)C)c1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(O)nc2CC(C)(C)C)c1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of 3-(2-fluoro-5-methoxyphenyl)-6-methoxy-2-neopentylpyridine (3.97 g) in DMF (10 mL) was added pyridinium chloride (7.56 g) at room temperature, and the mixture was stirred at 130° C. for 30 min. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the resulting white precipitate was collected by filtration. The crude crystals were washed with water and hexane to give the title compound (3.64 g) as a white amorphous solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[I:12].Br/[C:14](=[CH:19]\[CH3:20])/[C:15]([O:17][CH3:18])=[O:16].CN1C(=O)N(C)CCC1>C1COCC1>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH2:20][CH:19]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([I:12])[CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(O)c(I)c1
Reactant: C/C=C(\Br)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C=CCOc1ccc(C#N)cc1I
Temperature: 55 °C
Reaction time: 4.5 h
Yield: 73.7 %

Procedure:
To a cooled (0° C.) suspension of NaH (1.5 g of 60% suspension in mineral oil, 38 mmol) in THF (80 mL) was added a solution comprised of 4-hydroxy-3-iodo-benzonitrile (8.4 g, 34 mmol) (reference example 12), methyl bromo-crotonate (6.65 mL tech. grade, approx. 51 mmol) and DMPU (10 mL) in THF (20 mL). On complete addition, the cold bath was removed and replaced with an oil bath. The reaction mixture was heated to 55° C. and stirred at this temperature for 4.5 hr, cooled to room temperature and acidified with 2M aqueous HCl. The mixture was then diluted with ethyl acetate, washed sequentially with water and brine, dried over MgSO4 and concentrated. The residue was triturated with hexane several times, leaving 8.6 g of the title compound as a solid. 1H NMR (CDCl3) d 3.78 (s, 3H), 4.80 (dd, J=4, 1 Hz, 1H), 6.35 (dt, J=16, 1 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 7.05 (dt, J=16, 4 Hz, 1H), 7.60 (dd, J=8, 1 Hz, 1H), 8.06 (d, J=1 Hz, 1H). MS (EI) m/z 343 (M)+.