Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:33])[N:13]2[C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][CH:19]=1)C1C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:33])[N:13]2[C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:22][CH:23]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-n2c(=O)[nH]c3c(N(Cc4ccccc4)Cc4ccccc4)ncnc32)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1ccc(-n2c(=O)[nH]c3c(N)ncnc32)cc1
Temperature: 60 °C
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl 4-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl) carbamate (39) (3 g, 5.6 mmol) in MeOH (120 mL) was added Pd(OH)2/C (3 g, 20 wt %) and 6 drops of con. HCl. The resulting mixture was purged with H2 (2×) and heated to 60° C. overnight under H2 atmosphere. The mixture was cooled to r.t., filtered through a Celite pad, and the solvent was removed in vacuo to obtain tert-butyl 4-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (40) (2 g, 100%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 357.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[CH3:9][C:8]([C:4]1[CH:3]=[CH:2][C:1]([OH:7])=[CH:6][CH:5]=1)=[O:10]
Reactant: Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1ccc(O)cc1

Procedure:
acylating phenol with acetic anhydride to produce 4-hydroxyacetophenone; and
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[CH3:35][C:36]([CH2:38][C:39]([C:41]1[O:45][CH:44]=[CH:43][CH:42]=1)=[O:40])=O>>[O:45]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:39](=[O:40])/[CH:38]=[C:36](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:35]
Reactant: CC(=O)CC(=O)c1ccco1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)c1ccco1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 630 mg (1.31 mmol) of Intermediate 45 (as the TFA salt) and 200 mg (1.31 mmol) of 1-(2-furyl)-1,3-butadione (purchased from Acros Organics) to yield 230 mg (35% yield) of Example 29 as a light brown solid: TLC (DCM/MeOH (4:1): Rf=0.62; 1H NMR (DMSO-d6, 300 MHz) δ11.07 (d, 1H, J=8.7), 7.88 (m, 2H), 7.69 (d, 1H, J=1.0), 7.48 (m, 3H), 7.09 (d, 2H, J=8.5), 6.86 (m, 3H), 6.52 (d, 1H, J=1.5), 5.33 (s, 1H), 4.13 (t, 2H, J=6.6), 4.03 (m, 1H), 3.14 (m, 1H), 2.87 (t, 2H, J=6.6), 2.70 (dd, 1H, J=13.6, 9.0), 2.34 (s, 3H), 1.62 (s, 3H); low resolution MS (ES+)m/e 501.2 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3F)oc2C)c1)C(=O)O
Yield: 47 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole, the title compound was obtained in 47% yield as a yellow solid. MS: (M+H)+ 423.3.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Cl>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: ClCc1ccccn1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccccn2)c(=O)[nH]c1=O
Yield: 35.6 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (125 mg, yield: 35.6%).
Reaction SMILES: C(N(CC)CC)C.C([O-])(=O)C.[Zn+2:12].C([O-])(=O)C.[C:17]1([CH:23]2[O:27][CH:26]([C:28]([Cl:31])([Cl:30])[Cl:29])[NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:32](=[S:34])=[S:33]>>[C:17]1([CH:23]2[O:27][CH:26]([C:28]([Cl:31])([Cl:30])[Cl:29])[N:25]([C:32]([S-:34])=[S:33])[CH2:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[C:17]1([CH:23]2[O:27][CH:26]([C:28]([Cl:31])([Cl:30])[Cl:29])[N:25]([C:32]([S-:34])=[S:33])[CH2:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[Zn+2:12]
Reactant: ClC(Cl)(Cl)C1NCC(c2ccccc2)O1
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Product: S=C([S-])N1CC(c2ccccc2)OC1C(Cl)(Cl)Cl
Temperature: 50 °C
Yield: 58 %

Procedure:
A mixture of 30.3 g (0.3 mole) triethylamine, 18.3 g. (0.1 mole) zinc acetate, 55.0 g. (0.206 mole) 5-phenyl-2-trichloromethyloxazolidine and 15.6 g. (0.206 mole) carbon disulfide was stirred at ambient temperatures for 17 hours and then was heated at 50° C, for 3 hours. A reddish amber-colored semi-solid was obtained after the volatile materials were distilled off at 50°/25 mm. Hg. The semi-solid was dissolved in methanol and the resulting solution added to water with vigorous stirring. The solids were filtered, air-dried, and redissolved in benzene. After drying the solution with magnesium sulfate, filtering the mixture and evaporating the solvent, 37 g. (58%) of the desired product (m.p. 91°-93° C.) was obtained; its infrared spectrum was consistent with the structure: Found: N, 3.86. Calc. for C22H18Cl6N2O2S4Zn: N, 3.74.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.[ClH:27]>CCOCC.O>[ClH:27].[OH:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:24])[N:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]32)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(O)cc3C(F)(F)F)[C@@H]2C1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C1c2c(cc(O)cc2C(F)(F)F)[C@@H]2CNCCN12
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (14 mg, 0.04 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 10 mg of a white solid. MS (ESI) 273 (M−Cl).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[N+:25]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[NH2:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Reaction time: 60 h

Procedure:
A 200 mL RBF was charged with (R)-3-(tert-butyldimethylsilyloxy)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine (4.10 g, 10.1 mmol) and palladium, 10 wt. % on activated carbon wet (0.179 ml, 2.03 mmol) under nitrogen. MeOH was added via syringe, and the atmosphere replaced with hydrogen via one or more balloons. The reaction was stirred rapidly for 60 h. The reaction was flushed with nitrogen, filtered through celite rinsing with 100 mL MeOH, and concentrated in vacuo. The crude material was treated with hexanes and passed through a Redi-Sep® pre-packed silica gel column (80 g) eluting with 0-40% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)benzenamine as a brown oil. MS m/z=375 [M+H]+. Calc'd for C18H29F3N2OSi: 374.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.S(Cl)([Cl:19])=O>ClCCl>[Cl:19][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (2.31 g, 10.03 mmol, 1.00 equiv) in dichloromethane (20 mL) and a solution of thionyl chloride (1.5 mL, 2.00 equiv) in dichloromethane (3 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2×25 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×15 mL of sodium bicarbonate aq. and 2×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 1.16 g (46%) of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate as a off-white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Br[CH:28]([CH3:39])[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].Cl>C(OCC)(=O)C>[C:8]([NH:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O:25][CH:28]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH3:39])=[O:24])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(Br)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(OC(=O)CCC(=O)CNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Triethylamine was added drop-wise to a stirred solution of 5-(Cbz-amino)-4-oxopentanoic acid (4.00 g; 15.0 mmol) and the product of 2a (3.65 g; 15.0 mmol) in ethyl acetate (50 mL). The stirred mixture was refluxed for 2 days under argon. After cooling to ambient temperature, 0.5 M HCl solution (50 mL) was added and the mixture was shaken thoroughly. The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solutions were washed with saturated NaHCO3 solution (2×15 mL) and saturated NaCl solution (1×15 mL), then dried (MgSO4). After filtration and evaporation an amber oil was obtained that was purified by flash chromatography on a 60×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL), collecting 8×100 mL fractions. Evaporation of fractions 3-5 resulted in 4.92 g (77%) product (oil).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19](=[O:24])C(F)(F)F)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:29]>CN(C)C=O.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19]([OH:24])=[O:29])=[C:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCn2c(c(C(=O)C(F)(F)F)c3ccccc32)C1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCn2c(c(C(=O)O)c3ccccc32)C1
Yield: 86.2 %

Procedure:
To a solution of 0.29 g (0.77 mmol) 10-(2,2,2-trifluoro-acetyl)-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 7 ml N,N-dimethylformamide were subsequently added 0.22 g (4.6 mmol) sodium hydride (50% in oil) and a solution of 0.070 ml (3.9 mmol) water in 1 ml N,N-dimethylformamide at room temperature. The reaction mixture was diluted with tert-butyl methyl ether after 2 h and extracted with 1 M sodium hydroxide solution (2×30 ml). The combined aqueous layers were acidified (pH 1-2) with 2 M hydrochloric acid at 0° C. and extracted with tert-butyl methyl ether (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (0.21 g, 86%) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI>C1COCC1>[CH3:10][C:9]1[C:2]([NH:1][CH3:11])=[N:3][CH:4]=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: Cc1cc(C#N)cnc1N
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1ncc(C#N)cc1C

Procedure:
6-Amino-5-methyl-nicotinonitrile (0.250 g, 1.88 mmol) was dissolved in 2.5 ml of abs. THF and treated at 0° C. with sodium hexamethyldisilazide-solution (1M in THF, 2.07 ml, 1.1 eq.) and, after 5 Min., 3 eq. of methyl iodide (0.35 ml). The mixture was allowed to react for 3 h at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=6/4) produced 0.225 g of the title compound as off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C([Li])(C)(C)C.CCCCC.[C:28]1(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CCOCC>[OH:34][C:28]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Reactant: O=C1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: OC1(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
A solution of 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 3b, 303 mg, 1.03 mmol) in ether (12.5 mL) was added to KH (42.9 mg, 1.07 mmol) at 0° C. After stirring at 0° C. for 20 minutes, the reaction mixture was cooled to -78° C. and a solution of tert-butyllithium in pentane (1.7 M, 0.22 mL, 2.1 mmol) was added dropwise. The reaction mixture was stirred at -78° C. for 30 minutes prior to the addition of cyclohexanone (0.22 mL, 2.1 mmol). The reaction was quenched by the addition of pH 7 buffer and the product was extracted into ethyl acetate, washed with water and brine, and dried over sodium sulfate. After removal of the solvent in vacuo, flash chromatography (silica, 5-10% 2M methanolic ammonia in dichloromethane) yielded 5-(1-hydroxycyclohex-1-yl)-3-(2-pyrrolidinylethyl)-1H-indole (116.4 mg, 36%); HRMS-FAB+ for C20H28N2O: calculated MH+ :313.22800; found MH+ :313.23151.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[C:13]([CH3:18])[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:14]2[CH:15]=[CH:16][C:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:12][C:13]=2[CH3:18])[CH:21]=1
Reactant: Cc1cc(S(=O)(=O)c2ccc(F)cc2)ccc1Br
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1C

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step i) and 5-chloro-2-methoxybenzene boronic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][O:11][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(CCCO)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(CCCOc2ccc(C#N)cn2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a stirred solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol (5.0 g, 31.7 mmol) in DMF (200 mL), was added NaH (60%; 1.73 g, 43.3 mmol) portion wise. Once the initial effervescence had subsided, the mixture was heated at 60° C. for 1 h, and then was cooled to rt. A solution of 6-chloronicotinonitrile (4.0 g, 28.9 mmol) in DMF (20 mL) was then added and the mixture was stirred for 16 h before quenching with saturated (satd.) aq. NaHCO3 (50 mL) and brine (50 mL). A precipitate was formed and was collected by vacuum filtration to afford 3.67 g of the product. The filtrate was concentrated to half the volume and a second crop of precipitate was recovered. The precipitates were combined to give 5.64 g (76%) of an orange solid, which was used without further purification. MS (ESI): mass calcd for C15H21N3O, 259.17; m/z found, 260.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.46 (dd, J=2.3, 0.8, 1H), 7.77 (dd, J=8.6, 2.3, 1H), 6.80 (dd, J=8.6, 0.8, 1H), 4.34 (t, J=6.6, 2H), 2.96-2.82 (m, 2H), 2.25 (s, 3H), 1.92-1.68 (m, 7H), 1.37-1.34 (m, 2H), 0.89-0.81 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:12])=[CH:4][N:3]=1.[CH3:13][NH2:14]>O1CCCC1.CO>[I:12][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]([NH:14][CH3:13])=[N:3][CH:4]=1
Reactant: CN
Reactant: CCCNc1nc(Cl)ncc1I
Solvent: CO
Solvent: C1CCOC1
Product: CCCNc1nc(NC)ncc1I
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 46.3 mg) in tetrahydrofuran (0.5 mL), a 9.8 mol/L solution of methylamine in methanol (0.5 mL) was added at room temperature, the reaction vessel was sealed, and then by using a microwave reaction system, the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 40 to 27% hexane in ethyl acetate) to obtain 5-iodo-N2-methyl-N4-propylpyrimidine-2,4-diamine (F222, 32.4 mg) as white solid.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([O:46][CH3:47])[CH:45]=1)[CH:41]=O>C1COCC1>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:41]=[CH:6][CH2:5][C:2]([OH:4])=[O:3])[CH:43]=[C:44]([O:46][CH3:47])[CH:45]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=CCC(=O)O)cc(OC)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 38.1 %

Procedure:
To a solution of (2-carboxyethyl)triphenylphosphonium bromide (13.7 g, 33 mmol) in dry THF (50 mL) was added NaHMDS (33 mL, 66 mmol) dropwise at −20° C. under N2 and the reaction stirred for 20 min. The reaction was cooled to −78° C. and 3,5-dimethoxybenzaldehyde (5.0 g, 30 mmol) was added, and the reaction mixture stirred overnight while warming to rt. The reaction was quenched with water and extracted with EtOAc. The aqueous layer was acidified to pH=2 with dilute HCl solution and extracted with EtOAc again. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 2.54 g (38%) of the title compound as an orange gum. [M+H] Calc'd for C12H14O4, 223. Found, 223.
Reaction SMILES: ClC(OC(Cl)=O)C.COC1C=C(OC)C=CC=1C[N:13]1[CH2:26][CH:25]([CH3:27])[N:16]2[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@@H:15]2[CH2:14]1.C(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:27][CH:25]1[N:16]2[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@@H:15]2[CH2:14][NH:13][CH2:26]1
Reactant: COc1ccc(CN2CC(C)N3Cc4ccccc4C[C@@H]3C2)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1CNC[C@H]2Cc3ccccc3CN12
Temperature: 0 °C
Yield: 56 %

Procedure:
1-Chloroethylchloroformate (0.050 ml, 0.47 mmol) was added to a solution of (11aR)-2,3,4,6,11,11a-hexahydro-2-(2,4-dimethoxybenzyl)-4-methyl-1H-pyrazino[1,2-b]isoquinoline (53 mg, 0.15 mmol) in 1,2-dichloroethane (1 ml) stirring at 0° C. The ice bath was removed and the reaction stirred at ambient temperature for 30 min. After refluxing an additional 2 h, the reaction was evaporated in vacuo. Methanol (1.0 ml) was added to the residue and the reaction refluxed under nitrogen for 1 h. Evaporation in vacuo afforded 75 mg of crude product. This crude product was transferred to a separatory funnel with CH2Cl2 and saturated NaHCO3. Extraction with CH2Cl2 (2×) and drying of the combined organic layers over MgSO4 afforded 42 mg which was further purified by flash chromatography (SiO2, 0.2 to 10% 2N N3 in MeOH/CH2Cl2) to give pure product (17 mg, 55%). MS (ESI) 203 (M+H).
Reaction SMILES: [N:1]([CH:4]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:13]=[CH:12][CH:11]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[N+]=[N-]>CO.[Pd]>[CH2:8]([CH:5]([CH2:6][CH3:7])[CH:4]([NH2:1])[C:10]1[N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[N:13]=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCC(CC)C(N=[N+]=[N-])c1ccnn1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)C(N)c1ccnn1-c1ccc(OC)cc1
Reaction time: 18 h
Yield: 97 %

Procedure:
A mixture of 5% Pd/C (300 mg) and 5-(1-azido-2-ethylbutyl)-1-(4-methoxyphenyl)-1H-pyrazole (882 mg, 2.95 mmol) in methanol (30 mL) was shaken on a Parr apparatus under 3 atm of H2 for 18 h. The reaction was filtered through a plug of Celite, washed well with methanol and concentrated in vacuo to yield the amine in 97% yield as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:30].[CH3:31][CH:32]([CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:33](O)=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:30].[ClH:30].[CH3:29][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:33](=[O:34])[CH:32]([CH3:31])[CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Reactant: CC(CCN1CCOCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)C(C)CCN3CCOCC3)cc(C(C)C(C)CCCCC)cc1OC2(C)C

Procedure:
A combination of 5.0 g. (12.6 mmole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 2.82 g. (12.6 mmole) of α-methyl-γ-morpholinobutyric acid hydrochloride, 2.78 g. (13.5 mmole) of dicyclohexylcarbodiimide and 250 ml. of methylene chloride was stirred at room temperature for 16 hours. The reaction mixture was cooled and the by-product of dicyclohexylurea was removed by suction filtration. The solvent was removed and the residue dissolved in a mixture of methylene chloride/cyclohexane and again filtered to remove a small amount of insoluble material. After evaporation of the solvents, the material was dissolved in methylene chloride and converted to the dihydrochloride salt by the addition of ethereal hydrogen chloride. The solvents were removed and the residue was recrystallized from a methylene chloride/diethyl ether mixture to give 4.2 g. (52%) of colorless crystals, m.p. 188°-192° C. The sample was shown to be free of starting material by thin layer chromatography (10% MeOH/CHCl 3), and the infrared and nuclear magnetic resonance spectra were consistent with the proposed structure.