Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37].[Cr](O)(O)(=O)=O>C(OCC)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C:11]1=[O:37]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=[Cr](=O)(O)O
Solvent: CCOCC
Product: CCCCC[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CC(=O)CCCCC(=O)OC)OC1CCCCO1
Reaction time: 1 h

Procedure:
To a solution of crude (13E)-(9α,11α,15S)-6-oxo-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Reference Example 7) in 10 ml of diethyl ether was added 10 ml of a chromic acid solution (obtained from 760 mg of chromium trioxide, 2.56 g of manganese sulphate, 0.84 ml of sulphuric acid and 19 ml of water) at 0° to 5° C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was extracted with diethyl ether and the extract was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (17:3) as eluent to give 480 mg of the title compound having the following physical characteristic:
Reaction SMILES: [OH-].[K+:2].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:17]#[C:18]C(C)CO)[CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)=[O:6]>C(O)CCC>[C:17]([C:9]1[CH:10]=[C:11]([C:13]([O-:15])=[O:14])[CH:12]=[C:7]([CH:8]=1)[C:5]([O-:6])=[O:4])#[CH:18].[K+:2].[K+:2]
Reactant: COC(=O)c1cc(C#CC(C)CO)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: C#Cc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Yield: 97 %

Procedure:
Into a 5 liter four-necked flask equipped with a thermometer, a Dimroth condenser and a stirrer, 3 liters of n-butanol and 182 g (2.763 mole) of potassium hydroxide (85%) were placed and potassium hydroxide was dissolved into n-butanol by heating under the refluxing condition. To the resultant solution, 95 g (0.344 mole) of 4-[3,5-bis(methoxycarbonyl)phenyl]-2-methyl-3-butyn-1-ol synthesized above in (2) was added and the resultant mixture was heated under the refluxing condition for 30 minutes. The mixture was then cooled in an ice bath. The formed crystals were separated by filtration, washed twice with 1 liter of methanol and dried at 60° C. in vacuo and 88.87 g (the yield: 97%) of dipotassium 5-ethynylisophthalate was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: BrCc1ccccn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccn3)C2=O)cn1
Yield: 50 %

Procedure:
Prepared as in Example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione and 2-(bromomethyl)pyridine. Yield: 50%. 1H NMR (CDCl3, 400 MHz): δ 2.19 (s, 3H), 2.41 (s, 3H), 4.12 (s, 2H), 4.71 (s, 2H), 5.05 (s, 2H), 7.72-7.23 (m, 4H), 7.92 (s, 1H) 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.68 μM.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=O)([O-])=O.C([O-])=O.[NH4+].[CH3:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][C:34]([CH:35]=O)=[C:29]3[N:28]=[C:27]2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:23][CH:22]=1>CO.CCOCC.[Pd]>[CH3:19][O:20][C:21]1[CH:44]=[CH:43][C:24]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][C:34]([CH2:35][N:1]4[CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]4=[O:9])=[C:29]3[N:28]=[C:27]2[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:23][CH:22]=1
Reactant: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc3c(C=O)ccnc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: CCCC1CC(=O)N(Cc2ccnc3c2nc(-c2ccccc2)n3Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde x225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to yield 0.79 g of 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x226.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[C:30]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([OH:32])=[O:31]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:27][C:9]1[CH:8]=[C:7]([C:38]2[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][C:30]([OH:32])=[O:31])=[CH:36][CH:37]=2)[CH:12]=[C:11]([Cl:13])[C:10]=1[CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]1=[O:26]
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)CCc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 95 °C
Yield: 124.8 %

Procedure:
Charge a vial with 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (0.30 g, 0.63 mmol), 4-(2-carboxyethyl)benzene boronic acid (0.123 g, 0.634 mmol) and Pd(Ph3)4 (0.073 g, 0.063 mmol) in 1,4-dioxane (5 mL) and 2 M Na2CO3 (1 mL) and heat to 95° C. for 16 hours. Cool the reaction, extract with ethyl acetate and water, dry the organic layer (Na2SO4) and purify by HPLC (5 to 95% acetonitrile in water with 0.1% trifluroacetic acid buffer) to afford 373 mg (62%) of the title compound: LC-MS (ES +) m/z=exact mass calcd for C26H29Cl2NO3 473, found 474 and 476 (M+1 and M+3, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[O:27]([CH2:34][CH2:35][CH2:36]Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:27]([CH2:34][CH2:35][CH2:36][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCCOc1ccccc1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(OCCCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)cc1

Procedure:
To a solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.07 g, 0.019 mole in 75 ml DMF), 10 g milled K2CO3 and 10 mg KI, was added a solution of 3-phenoxypropylbromide (4.78 g, 0.022 mole in 20 ml DMF).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([O:40][C:2]2[N:7]=[C:6]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Cl)n3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: Oc1cccc(F)c1
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Oc4cccc(F)c4)n3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 3.3 h

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D107) and 3-fluorophenol using a procedure similar to that described for D125 in Description 125 although the reaction time was 3.3 h. MS (ES): MH+ 535.4.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN(C=O)C>[CH:25]1([NH:28][C:7]2[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:21])[F:22])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC1CC1
Yield: 95.1 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 27, 1.83 ml (0.026 mol) of cyclopropylamine in 30 ml of DMF were reacted at room temperature affording 4.95 g of dark oil which was purified by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent to give 3.87 g (74.4%) of product as a yellow oil, nD25 1.4708.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([O:10][C:11]([F:14])([F:13])[CH3:12])=[CH:8][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[OH:24]O>CO>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([OH:24])=[CH:8][C:9]=2[O:10][C:11]([F:14])([F:13])[CH3:12])[CH2:3][CH2:2]1
Reactant: CC(F)(F)Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C1CC1
Reactant: OO
Solvent: CO
Product: CC(F)(F)Oc1cc(O)cnc1C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the crude 2-cyclopropyl-3-(1,1-difluoroethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 268, 412 mg, 1.27 mmol) was added methanol (20 mL), and the stirred solution cooled in an ice bath. To the solution was added hydrogen peroxide solution (35% in water) (0.15 mL, 1.52 mmol) over 2 minutes. The solution was allowed to warm slowly to room temperature over 18 hours. The reaction was quenched by addition of 1M aqueous sodium thiosulfate solution (50 mL), and rapidly stirred for 15 minutes. The organics were removed in vacuo, and brine (50 mL) was added. The aqueous was extracted into ethyl acetate (3×100 mL). The combined organics were dried over magnesium sulfate, filtered and the solvent removed to leave an orange oil. The oil was purified through a plug of silica, eluting with 1:1 ethyl acetate:heptane to provide the title compound a white solid (155 mg, 57%).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[N:38]=[C:37]([C:39]([O:41]C)=O)[C:36]([C:43]([O:45]C)=O)=[N:35]1)(=O)C1C=CC=CC=1.[NH3:47].CO.[NH3:50]>>[C@H:11]1([N:34]2[N:35]=[C:36]([C:43]([NH2:47])=[O:45])[C:37]([C:39]([NH2:50])=[O:41])=[N:38]2)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: COC(=O)c1nn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)nc1C(=O)OC
Reactant: N
Solvent: CO
Product: NC(=O)c1nn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)nc1C(N)=O
Temperature: 95 °C
Yield: 89 %

Procedure:
Compound 31 (6.0 g, 9.5 mmol) was dissolved in MeOH/NH3 (dry MeOH sat. with anhydrous NH3 at 0° C., 60 mL) were placed in a steel reaction vessel. The vessel was heated at 95° C. for 16 h. The reaction vessel was cooled, opened carefully and the NH3 was allowed to evaporate at room temperature. The MeOH was evaporated to dryness and the residue was triturated with hot toluene (3×50 mL) and filtered. The brown residue was crystallized from aqueous EtOH (95%) to furnish 2.40 g (89%) of 32: mp 210-212° C.; 1H NMR (Me2SO-d6) δ 3.45-3.59 (m, 2H, C5′H), 3.98 (m, 1H, C4.H), 4.25 (m, 1H, C3.H), 4.54 (m, 1H, C2′H), 4.78 (t, 1H, C5′OH, D2O exchangeable), 5.27 and 5.67 (2d, 2H, C2′,3′OH, D2O exchangeable), 5.89 (d, 1H, J1′,2′=3.85 Hz, C1′H), 8.05 and 9.05 (2br s, 4H, 2 CONH2). Anal. CaIc. for C9H13N5O6 (287.23): C, 37.63; H, 4.56; N, 24.38. Found: C, 37.52; H, 4.19; N. 24.59.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH2:10][C@H:11]1[C:16]2[C:17]([CH3:23])=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:15]=2[CH2:14][C@@H:13]([CH2:24][OH:25])[O:12]1)=[N+]=[N-]>C(OCC)C>[NH2:7][CH2:10][C@H:11]1[C:16]2[C:17]([CH3:23])=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:15]=2[CH2:14][C@@H:13]([CH2:24][OH:25])[O:12]1
Reactant: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CN
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Lithium aluminum hydride (1.1 mL of a 1.0M solution in diethyl ether, 1.1 mmol) is added dropwise to a solution of 289 mg (1.1 mmol) of [1R,3S] 1-azidomethyl-3,4-dihydro-3-hydroxymethyl-5-methoxy-8-methyl-1H-2-benzopyran, the product of Step 4 of Example 142, in 10 mL of anhydrous diethyl ether at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 40 min. The reaction mixture is cooled to 0° C. and quenched by the sequential addition of 42 μL of water, 42 μL of 15% aqueous sodium hydroxide solution and 126 μL of water. The solution is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Li]CCCC.CN([CH:35]=[O:36])C.[NH4+].[Cl-]>CCOC(C)=O.O.CCOCC.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:3]1[C:4]([CH3:18])=[C:5]([CH3:17])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH3:8])[C:2]=1[CH:35]=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(C)c(OCc2ccccc2)c(Br)c(C)c1OCc1ccccc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(OCc2ccccc2)c(C=O)c(C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
2-Bromo-1,4-bis(benzyloxy)-3,5,6-trimethylbenzene (5.002 g, 12.16 mmol) was dissolved into 25 mL toluene and 25 mL Et2O and cooled to 0° C. To this stirred yellow solution was added 8.2 mL n-BuLi (1.6 M in hexanes, 12.76 mmol, 1.05 equiv.) over ten minutes to give a clear yellow solution. After 20 min at 0° C. the solution became cloudy. To this slightly cloudy solution was added DMF (3 mL, 40 mmol, 2.8 g) which clarified the solution instantly upon addition. After overnight stirring, 50 mL 20% aqueous NH4Cl was added followed by 100 mL H2O and 100 mL EtOAc. The layers were separated and the aqueous phase extracted 3×100 mL EtOAc and the combined organics washed 2×50 mL saturated aqueous NaCl, dried over Na2SO4 and concentrated to a yellow oil which solidified to give 2,5-bis(benzyloxy)-3,4,6-trimethylbenzaldehyde as a pale brown solid (3.90 g). MS M++H=361 m/z; 1H NMR (400 MHz, CDCl3) d=10.51 (s, 1H), 7.51-7.37 (m, 10H), 4.87 (s, 2H), 4.74 (s, 2H), 2.55 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H) ppm.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>O>[CH:1]([NH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)=[O:2]
Reactant: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1N
Reactant: O=CO
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1NC=O
Temperature: 50 °C

Procedure:
1 g of powdered iron was added in portions to a mixture comprising 1 g of 4-(3-nitro-4-methoxybenzyl)amino-6-chloroguinazoline, 4 ml of acetic acid, 4 ml of water and 40 ml of ethanol, while heating the mixture under mild reflux. The obtained mixture was heated under reflux for 2 hours and filtered to remove insolubles. Concentrated hydrochloric acid was added in portions to the brown filtrate obtained above to give a yellow transparent solution. This solution was cooled with ice to precipitate crystals. The crystals were recovered by filtration and dried to give 1.1 g of 4-(3-amino-4-methoxybenzyl)amino-6-chloroquinazoline hydrochloride. This hydrochloride was dissolved in ethanol/water and the obtained solution was made alkaline by adding a 15% aqueous solution of sodium hydroxide in portions. Water was added to the resulting alkaline solution in portions to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 770 mg of 4-(3-amino-4-methoxybenzyl)amine-6-chloroquinazoline (an aniline derivative). Separately, 1 ml of formic acid was dropped into 2 ml of acetic anhydride under cooling with ice and the obtained mixture was heated at 50° C. for 15 minutes and immediately cooled with ice, followed by the addition of the above aniline derivative as such (in a crystalline state). The obtained mixture was reacted at that temperature for one hour and at room temperature for one hour, followed by the addition of water. The crystals thus formed were recovered by filtration, washed with water and dried to give 130 mg of the title compound.
Reaction SMILES: C(OC([CH:6]1[CH2:13][CH:12]2[NH:14][CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7]1)=O)C.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17]([CH:9]1[CH:8]2[N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]([CH2:13][CH2:6][CH2:7]2)[CH2:11][CH2:10]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C1CC2CCCC(C1)N2
Solvent: CCO
Product: CCOC(=O)CN1C2CCCC1C(C(=O)OCC)CC2
Yield: 100 %

Procedure:
To a 250 mL round-bottomed flask equipped with a condenser and nitrogen inlet were added 5.59 g (28.36 mmol) ethyl-9-azabicyclo[3.3.1]nonane-3-carboxylate, 142 mL ethanol, and 9.47 g (56.72 mmol) ethyl bromoacetate. The reaction was refluxed 3 days, cooled, and evaporated. The residue was partitioned between methylene chloride and aqueous sodium hydroxide, and the organic layer was dried over sodium sulfate and evaporated. The residue was filtered through silica gel using ethyl acetate to afford an oil, 4.835 g (100% yield crude), as a mixture of diastereomers.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C)C1(C(C2C=CC=CC=2)NC(=O)C2C(C)=CC=CC=2C)CCOC1.[Cl:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[C:46]([CH3:53])[CH:45]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([NH:1][CH:2]([C:3]2([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:49])=[C:46]([CH3:53])[CH:45]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCOC1
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (80 mg, 0.37 mmol), 4-chloro-2-methylbenzoic acid (68 mg; 0.40 mmol), HOBt (61 mg; 0.40 mmol) and PS-DCC (310 mg of 1.3 mmol/g loading, 0.40 mmol) in DCM (4 ml) was shaken overnight. Saturated aqueous sodium bicarbonate was added and the mixture separated with a phase-sep cartridge and the organics applied directly to SCX resin. Elution with DCM, methanol and then 1M ammonia in methanol, followed by chromatography eluting with 12-100% ethyl acetate-pentane (SP4 Biotage) afforded the title product (64 mg; 43%). 1H NMR (CDCl3) δ: 0.9-1.0 (1H, m), 1.25-1.40 (1H, m), 1.4-1.6 (2H, m), 1.6-1.75 (2H, m), 1.8-1.9 (2H, m), 2.22 (6H, s), 2.41 (3H, s), 5.09 (1H, d, J=5 Hz), 7.07 (1H, d, J=5 Hz), 7.2-7.4 (8H, m). Mass Spectrum (Electrospray LC/MS): Found 371 (MH+). C22H2735ClN2O requires 370. Ret. time 2.26 min. The title product was converted to the corresponding hydrochloride salt.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)([F:4])[F:3].[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C.[Cu](I)I>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:20]#[C:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([F:4])[F:3]
Reactant: C#Cc1ccccc1
Reactant: FC(F)(F)Sc1ccccc1I
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: FC(F)(F)Sc1ccccc1C#Cc1ccccc1
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A suspension of PdCl2PPH3 (0.027 g, 0.063 mmol) and copper iodide (0.0035 g, 0.018 mmol) in 3 ml of triethylamine was charged into a 50-ml eggplant flask equipped with a stirrer. To this suspension, a solution of (trifluoromethyl)(2-iodophenyl)sulfide (0.57 g, 1.9 mmol) prepared in Example 1 and phenylacetylene (0.23 g, 2.2 mmol) in 2 ml of triethylamine was added dropwise at room temperature, and the mixture was stirred overnight. After completion of the reaction, a solvent was removed, water was added to the obtained residue, and the mixture was extracted three times with ether. The obtained organic layers was collected and washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (Benzen/Hexane=20/80) to give target (trifluoromethyl)-(2-(2-phenylethynyl)phenyl)sulfide (0.5 g, 96%).