Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[NH:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]3([C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:36][NH:35][CH2:34]3)[CH2:30][CH2:29]1)=[O:27])[CH2:22]2.Cl>C(Cl)Cl>[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[NH:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]3([C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:36][N:35]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:34]3)[CH2:30][CH2:29]1)=[O:27])[CH2:22]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A vial, equipped with a flea stir bar, was charged with methanesulfonyl chloride (4.5 μL, 58 μmol), DIEA (15 μL, 90 μmol) and CH2Cl2 (1 mL). A solution of N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (25 mg, 53 μmol) in CH2Cl2 (1 mL) was added and the mixture was stirred overnight. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford N-(2-adamantyl)-2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (8 mg, 33%). LC-MS Method 1 tR=1.89 min, =458; 1H NMR (CDCl3) δ=1.60-2.15 (18H), 2.92 (s, 3H), 3.13 (m, 2H), 3.51 (s, 2H), 3.90 (d, 2H), 3.99 (s, 1H), 4.45 (s, 2H), 4.88 (1H), 7.05-7.40 (4H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH3:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CS[C:21]1[NH:22][CH:23]=[C:24]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[C:25](=[O:27])[N:26]=1>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH3:16])[C:21]3[NH:22][CH:23]=[C:24]([CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[C:25](=[O:27])[N:26]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Reactant: CNCCc1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Product: CN(CCc1ccc(Oc2ccc(F)cc2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 125 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
2-[4-(4-fluoro-phenoxy)-phenyl]-ethyl-methyl amine (0.204 mmol, 1 eq) and 2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.082 mmol, 0.4 eq) were dissolved in dry ethanol (200 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-10% in 30CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(4-fluoro-phenoxy)phenyl]-ethyl-methyl-amino}-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.042 mmol, yield: 20%, HPLC-MS/UV: [M+H]=432.14; rt: 10.14 mins; purity: 97%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.89 (t, J=7.17, 2H), 3.59 (s, 2H), 3.69-3.77 (m, 2H), 6.86-7.05 (m, 5H), 7.10-7.18 (m, 2H), 7.23-7.30 (m, 2H), 7.69 (s, 1H), 8.61 (s, 1H), 9.02-9.05 (m, 1H), 9.95 (br.s., 1H)
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:16]#[N:17].[Na+]>CS(C)=O>[C:16]([CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:17]
Reactant: [C-]#N
Reactant: COC(=O)c1cc2cccc(CBr)c2o1
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2cccc(CC#N)c2o1

Procedure:
A solution of 11.92 g of methyl 7-bromomethylbenzofuran-2-carboxylate and 5.57 g of sodium cyanide in 150 ml of dimethyl sulphoxide is stirred at room temperature over 1 hour. The reaction mixture is poured onto water and extracted with ethyl acetate (3×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (dichloromethane); Rt=3.86.
Reaction SMILES: [Br:1]Br.[C:3]([O-:6])(=[O:5])[CH3:4].[Cl:7][C:8]([Cl:19])([Cl:18])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11]>C(Cl)(Cl)(Cl)Cl.C([O-])(=O)C.[Ag+]>[C:3]([O:6][C:10]([CH2:11][Br:1])([CH2:9][C:8]([Cl:18])([Cl:19])[Cl:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:5])[CH3:4]
Reactant: C=C(CC(Cl)(Cl)Cl)c1ccccc1
Reactant: BrBr
Reactant: CC(=O)[O-]
Agent: [Ag+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OC(CBr)(CC(Cl)(Cl)Cl)c1ccccc1
Reaction time: 0.5 h

Procedure:
Silver acetate (17.0 grams; 0.10 mole) was mixed with 200 ml. of carbon tetrachloride and the mixture cooled in an aqueous alcohol bath to about -11° to -13° C. A solution of bromine (16.0 grams; 0.10 mole) in 100 ml. of carbon tetrachloride was added dropwise to the acetate solution while maintaining the reaction mixture temperature below about -11° C. Upon the completion of the bromine addition, the reaction mixture was stirred at temperatures below about -11° C. for about 30 minutes. Following this period, a solution of α-(2,2,2-trichloroethyl)styrene (11.2 grams; 0.05 mole) in 100 ml of carbon tetrachloride was added dropwise to the reaction mixture over a period of about 1 hour, while maintaining the reaction mixture temperature below about 5° C. The reaction mixture was warmed to ambient temperatures and stirred for a period of from about 1 to about 15 hours. Following this period the reaction mixture was filtered and the recovered silver halide precipitate extracted with methylene chloride. The extract was combined with the filtrate and the mixture washed successively with 5% NaHSO3 (3-100 ml. portions) and 100 ml. of water and then dried over sodium sulfate. The organic product layer was then evaporated in vacuo to obtain the desired α-(bromomethyl)-α-(2,2,2-trichloroethyl)benzyl acetate as a light yellow oil.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15]C(O)[CH2:13][CH2:12]1.C(OC(C)C)(C)C.O1CCOCC1>>[C:1]([O:9][CH:10]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: OC1CCNCC1
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: O=C(OC1CCNCC1)c1ccccc1
Yield: 65 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), piperidin-4-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and diisopropyl ether/1,4-dioxane (3/1) (5.0 ml) was heated to reflux for 46 hours, and as a result, piperidin-4-yl benzoate was obtained at a yield of 65%. The yield of N-benzoylpiperidin-4-yl benzoate was 30%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:15]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CS(O[CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[Cl:1][C:2]1[C:10]2[N:9]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:15]3)=[O:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCOS(C)(=O)=O
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3c(Cl)cccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21
Temperature: 70 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-{[(4-chloro-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (1.7 g) and 4-methoxybutyl methanesulfonate (754 mg) were dissolved in DMA (50 ml), cesium carbonate (1.7 g) was added, and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was poured into ice water (100 ml), and the mixture was extracted twice with ethyl acetate (100 ml). The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a less polar fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced is pressure to give 1-tert-butyl 3-methyl(3R,5S)-5-[{[7-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (200 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O.[Cl:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([SH:26])[NH:25][C:21]=2[CH:20]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])[NH:25][C:21]=2[CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: NCCCCCSc1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 133.2 %

Procedure:
1.5 g of the compound obtained in Example 17a and 0.93 g of 5-chloro-2-mercaptobenzimidazole were refluxed for 5 hours in 20 ml of acetonitrile containing 0.55 g of triethylamine. The reaction mixture was cooled to room temperature, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 1.81 g of the title compound (yield: 91%). Subsequently, the product was added with 0.85 g of hydrazine hydrate and 25 ml of methanol and refluxed for 5 hours. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated, washed with chloroform and then concentrated again to obtain 1 g of the title compound (crude product).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][C:3]=1[CH3:11].[OH-:12].[Na+].C[OH:15]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:15])=[O:12])=[CH:4][C:3]=1[CH3:11]
Reactant: [OH-]
Reactant: Cc1cc(CC#N)ccc1F
Reactant: CO
Agent: [Na+]
Solvent: O
Product: Cc1cc(CC(=O)O)ccc1F

Procedure:
2-(4-Fluoro-3-methylphenyl)acetonitrile (1 g) and sodium hydroxide (0.8 g) were combined in a mixture of methanol (10 mL) and water (3 mL). The resulting mixture was then heated at reflux overnight. The reaction was concentrated in vacuo and the residue dissolved in water (25 mL). The aqueous phase was washed with ether (2×25 mL), acidified with concentrated hydrochloric acid and extracted with ether (3×25 mL). The combined organic solutions were washed with brine, dried over sodium sulphate, filtered and evaporated in vacuo to afford the subtitled compound as a white solid. Yield 1.1 g.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.[OH:40][CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([OH:45])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:40][CH2:41][C:42]([CH3:47])([CH3:46])[C:43]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@H:6]3[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]3)[CH:26]=[CH:25][C:24]=2[CH3:27])=[CH:34][CH:33]=1)=[O:45]
Reactant: CC(C)(CO)C(=O)O
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(=O)C(C)(C)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
To a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-aminobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (19, 55 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (18 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.30 mmol) were combined in DMF (1 mL) and stirred for 4 hours at room temperature. The reaction quenched with saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in MeOH and treated with a few drops of NaOMe (25 wt % in MeOH) for 1 hour. The reaction was concentrated under vacuum, and the residue was purified by prep HPLC (C18 30×100 mm column, 5-40% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) to give the title compound 21 as a white solid (22 mg, 41% yield). 1H NMR (400 MHz, MeOH-d4) δ ppm 6.98-7.22 (m, 7 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.1 Hz, 1 H), 3.90-3.99 (m, 2 H), 3.49 (s, 2 H), 3.35-3.46 (m, 3 H), 3.19 (t, J=6.9 Hz, 2 H), 2.58 (t, J=7.5 Hz, 2 H), 2.18-2.23 (m, 3 H), 2.14 (s, 3 H), 1.60 (s, 2 H), 1.46-1.57 (m, 2 H), 1.11 (s, 6 H). MS (ES+) [M+H]+=532.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH2:7]=O.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1>O.C(Cl)Cl>[CH:10]12[CH2:9][CH:13]([CH:12]=[CH:11]1)[CH2:7][N:2]2[CH2:3][C:4]([NH2:6])=[O:5]
Reactant: C1=CCC=C1
Reactant: C=O
Reactant: NCC(N)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: NC(=O)CN1CC2C=CC1C2
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A solution of glycinamide hydrochloride 22.1 g, 0.20 mol) in water is treated with 37% formalin (23.0 g, 0.28 mol formaldehyde) cooled to 10° C., treated with cyclopentadiene (26.4 g, 0.40 mol), stirred for 3 hours at 5°-10° C., and diluted with methylene chloride. The phases are separated. The aqueous phase is extracted with methylene chloride and basified with 10% NaOH to pH 12 with cooling. The aqueous basic phase is extracted with methylene chloride. The methylene chloride extracts of the basic aqueous phase are combined and concentrated in vacuo to give the title product (N-carboxamidomethylazanorbornene) as a solid, 17.6 g, mp 74°-96° C. which can be purified by sublimation at 120° C./0.55 torr. The compound is identified by NMR and mass spectral analyses.
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([F:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:13]N)[CH:4]=1.O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[C:11]([F:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:21]1[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C:16]=1[NH:13]2
Reactant: NNc1cc(Br)c(F)cc1C(=O)O
Reactant: CCOC(=O)C1CCCC(=O)C1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A mixture of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride (5.37 g, 18.8 mmol), ethyl 3-oxocyclohexanecarboxylate (3.52 g, 20.7 mmol) and acetic acid (3.23 mL, 56.4 mmol) in toluene (90 mL) was heated at 110° C. for 20 h. The solvent was removed under reduced pressure, and the residue was diluted with toluene (43 mL) and trifluoroacetic acid (11 mL). The mixture was stirred at 90-94° C. overnight. The cooled mixture was diluted with EtOAc, sonicated, and the precipitate was collected by filtration. The filtrate was concentrated and resuspended in EtOAc with sonication, resulting in another precipitate which was also collected by filtration and washed with EtOAc. The combined solids were triturated twice with MeOH to give a solid. The combined filtrates were concentrated and the residue was triturated with MeOH to give additional solid. The solids were combined to give 5-bromo-2-ethoxycarbonyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a pale yellow solid (3.38 g). Mass spectrum m/z 384, 386 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=1[O:4][CH2:5][O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=2[O:4][CH2:5][O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:25]=[CH:24][C:23]=1[C:37]1[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCOc1cc(C(F)(F)F)ccc1Br
Product: C[Si](C)(C)CCOCOc1cc(C(F)(F)F)ccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (2-((2-bromo-5-(trifluoromethyl)phenoxy)methoxy)ethyl)trimethylsilane and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine. MS (ESI): mass calcd. for C23H25F4N3O2Si, 479.17; m/z found, 480.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55-8.48 (m, 2H), 7.60-7.51 (m, 3H), 7.48-7.36 (m, 3H), 5.33-5.29 (d, J=1.0, 2H), 3.73-3.66 (m, 2H), 0.93-0.84 (t, J=8.0, 2H), −0.03-−0.07 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][O:75][C:76](=[O:94])[C@@H:77]([NH2:93])[CH2:78][C:79]1[CH:84]=[CH:83][C:82]([C:85]2[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=2)=[CH:81][CH:80]=1.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:20])[NH:93][C@H:77]([C:76]([O:75][CH3:74])=[O:94])[CH2:78][C:79]2[CH:80]=[CH:81][C:82]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=3)=[CH:83][CH:84]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester, HBTU and DIEA were dissolved in DMF (20 mL). (S)-2-Amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester was added and the mixture stirred at r.t. for 16 h. The reaction mixture was poured into 1 N HCl and extracted with ethyl acetate. The organic extracts were combined and washed with 1 N HCl and 10% sodium carbonate, concentrated and purified by column chromatography on silica gel (hexanes-ethyl acetate) to afford the product (4.9 g). LCMS (m/z) 851.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16]>>[NH2:20][C:18]1[N:17]=[C:15]([NH2:16])[C:12]2[CH2:13][CH:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][CH2:10][C:11]=2[N:19]=1
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(Cc2ccccc2)CC1
Product: Nc1nc(N)c2c(n1)CCC(Cc1ccccc1)C2

Procedure:
For example, when n is the bridging group --CH2 --, an appropriately substituted or unsubstituted phenylmethyl bromide, for example, 2-chlorophenylmethyl bromide, is reacted with triphenylphosphine in toluene, affording the corresponding phenylmethyltriphenylphosphonium bromide. The so-prepared phosphonium bromide is then treated with n-butyllithium, and reacted with 1,4-cyclohexanedione mono-ethylene ketal, yielding the appropriate 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane. The 8-phenylmethylene-1,4-dioxaspiro[4.5]-decane is in turn reduced with hydrogen gas in the presence of 10% palladium on charcoal, giving the corresponding 8-phenylmethyl-1,4-dioxaspiro[4.5]-decane. The 1,4-dioxaspiro functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 2 provides a detailed description of how this reaction is conducted.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:33]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-[2-({2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-phenyl]-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 3-(4-methylpiperazin-1-yl)aniline (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.054 g, 50%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (d, J=6.6 Hz, 1H), 7.55-7.51 (m, 1H), 7.38-7.28 (m, 3H), 7.24-7.18 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 6.71-6.64 (m, 2H), 6.56 (d, J=8.2 Hz, 1H), 6.37 (d, J=7.7 Hz, 1H), 5.22 (t, J=6.1 Hz, 1H), 4.72 (d, J=6.0 Hz, 2H), 3.31 (s, 3H), 3.28-3.23 (m, 4H), 3.00 (s, 3H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:19])([N+:16]([O-])=O)[CH3:15])=[CH:9][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH2:16])([CH3:15])[CH3:19])=[CH:9][CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)COc1ccc(CC(C)(C)[N+](=O)[O-])cc1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)COc1ccc(CC(C)(C)N)cc1
Yield: 28 %

Procedure:
A solution of ethyl(4-[2-methyl-2-nitropropyl]phenoxy)ethanoate (3.6 g, 12.8 mmol) in ethanol (35 mL) was charged with platinum oxide (0.72 g) and hydrogenated on a Parr shaker using 60 psi of hydrogen for 72 h at room temperature. The catalyst was filtered and the solution concentrated in vacuo. The resulting residue was purified by flash chromatography over silica gel eluting with5% MeOH/CHCl3/NH3 to provided 0.9 g (28%) of a clear oil. MS (FD+): m/z 251.