Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[Cl:13].[C:15]([C:17]1[C:25]([CH3:26])=[CH:24][C:20](C(O)=O)=[CH:19][C:18]=1[CH3:27])#[N:16]>>[Cl:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([C:20]1[CH:24]=[C:25]([CH3:26])[C:17]([C:15]#[N:16])=[C:18]([CH3:27])[CH:19]=1)=[O:14]
Reactant: COC(=O)Cc1ccc(OC)cc1Cl
Reactant: Cc1cc(C(=O)O)cc(C)c1C#N
Product: COc1ccc(CC(=O)c2cc(C)c(C#N)c(C)c2)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 138, steps 1 and 2, from (2-chloro-4-methoxy-phenyl)-acetic acid methyl ester and 4-cyano-3,5-dimethyl-benzoic acid (CAS [90924-01-0]). Orange solid. MS (m/e, ISP neg. ion)=312.1 [M−H+].
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.Cl.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:16][CH:15]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
AlCl3 (26.7 g, 0.200 mol) was added in one portion to a stirred mixture of succinic anhydride (10.0 g, 0.100 mol) in bromobenzene (97.0 g) at −10° C. under N2 atmosphere. The reaction temperature was maintained at −10° C. for 1 hour and was then allowed to warm to room temperature. The mixture was stirred at room temperature overnight and poured into ice water. HCl (1M) was added slowly until pH 5. The mixture was extracted with ethyl acetate (150 mL×2). The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was washed with ether to afford 4-(4-bromophenyl)-4-oxobutanoic acid (16.0 g, 62%) as a white solid. 1H NMR (300 MHz, DMSO) δ 12.15 (br s, 1H), 7.90 (d, J=8.7, 2H), 7.73 (d, J=8.7, 2H), 3.22 (t, J=6.0, 2H), 2.55 (t, J=6.0, 2H).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7](=[NH:9])[NH2:8])=[CH:3]1.[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([C:4]2[CH:5]=[CH:6][O:2][CH:3]=2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccoc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2ccoc2)ns1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
To a solution of furan-3-carboximidamide hydrochloride (2.00 g, 13.6 mmol) and perchloromethyl mercaptan (1.47 ml, 13.6 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.72 g, 68.0 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 0.82 g (32.2%) of the desired product as an oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[C:4]([CH3:9])[CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:6][C:5]([CH2:7][OH:8])=[C:4]([CH3:9])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1cc(Br)sc1CO
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: 100 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of 62.5 (0.100 g, 0.48 mmol), 4-(trifluoromethyl)benzeneboronic acid 61.1 (0.183 g, 0.97 mmol), K2CO3 (0.200 g, 1.45 mmol), and Pd(PPh3)4 (0.056 g, 0.05 mmol) in toluene (3.2 mL) was stirred overnight at 100° C. The mixture was cooled to room temperature, filtered through a pad of silica gel (EtOAc), and concentrated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 62.6 (0.063 g, 48%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, 2H), 7.61 (d, 2H), 7.14 (s, 1H), 4.79 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])(O)[CH3:10])=[CH:5][CH:4]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])=[CH2:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(O)c2sc(C)nc2C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C=C(c1ccc(OC)cc1)c1sc(C)nc1C
Reaction time: 2 h

Procedure:
1- (4-Methoxyphenyl) -1- (2, 4-dimethyl-5-thiazolyl) ethanol (3.69g) in chloroform (50ml) was treated with hydrogen chloride in dry diethyl ether (1M, 14.5ml). After 2 hours at room temperature, aqueous sodium hydrogen carbonate was added and the mixture was extracted with chloroform. The material thus obtained was purified by flash chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2cc3cnc(Br)cc3n2-c2ncccn2)cn1
Temperature: 210 °C
Yield: 87.3 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 27 mg 0.10 mmole) and 2-bromopyrimidine (24 mg, 0.15 mmole) were dissolved in DMA (0.7 ml) and potassium carbonate (20 mg, 0.14 mmole) and copper(I) iodide (4.0 mg, 0.022 mmole) were added. The reaction was placed under argon and heated by microwave at 210° C. for 60 minutes. The reaction was taken up in ethyl acetate (25 mL) and the solution washed with water (3×7 mL) and brine. The combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with ethyl acetate to afford the title compound (31 mg). 1H-NMR (CDCl3, 500 MHz): 3.95 (s, 3H), 6.73 (d, J=0.95 Hz), 7.34 (s, 1H) under 7.34 (t, J=5.04 Hz, 1H), 7.53 (s, 1H), 8.11 (t, J=0.95 Hz, 1H), 8.66 (d, J=0.95 Hz, 1H), 8.85 (d, J=5.04 Hz, 2H),
Reaction SMILES: [K+].[Br-].N1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][NH:14]C(=S)[SH-]CC2C=CC=CC=2)=C1.F[C:26]1C=CC(CCNC(=S)[SH-]C)=C[CH:27]=1>>[NH2:14][CH2:13][C:12]1[CH:27]=[CH:26][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: S=C(NCCc1c[nH]c2ccccc12)[SH-]Cc1ccccc1
Reactant: C[SH-]C(=S)NCCc1ccc(F)cc1
Agent: [Br-]
Agent: [K+]
Product: NCc1ccc2ccccc2c1

Procedure:
Compound 27 (1.00 g, 5.8 mmol) in THF (20 mL) was added slowly to a solution of LAH (1.76 g, 46.4 mmol) in THF (45 mL) at 0° C. The solution was allowed to warm to room temperature and the reaction was stirred overnight. The reaction was cooled to 0° C. and quenched with H2O. The solids were filtered from the solution through celite and washed with hot THF. The filtrate was concentrated and the residue was dissolved in EtOAc (80 mL) and washed with 1 M HCl (3×30 mL). The aqueous layer was basified with 6 M NaOH to a pH of 12 and the precipitate was extracted with EtOAc (3×30 mL). The resulting organic solution was washed with brine (40 mL), dried with Na2SO4 and filtered. Concentration afforded a slightly yellow solid (510 mg, 56% yield). m.p. 55-56° C. 1H NMR (CDCl3) δ 7.80 (3H, ArH), 7.72 (s, 1H, ArH), 7.43 (m, 3H, ArH), 4.00 (s, 2H, ArCH2). 13C NMR (CDCl3) δ 140.6, 133.5, 132.5, 128.2, 127.7, 126.1, 125.8, 125.5, 125.1, 46.6. IR (KBr) vmax cm−1: 3362, 3291, 3050, 2915, 1950, 1596, 1507, 1358, 1273. GC: r.t.=8.97 min. EI-MS m/z (%) 157 (83, M+), 156 (100), 141 (15), 129 (49), 128 (40), 127 (24), 115 (10).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[O:9][N:8]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[O:9][N:8]=[C:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:28]
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: -15 °C
Yield: 95 %

Procedure:
168 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)-piperidinium hydrochloride obtained in step 1) above and 220 μl (3.1 eq.) of triethylamine were dissolved in 1 ml of dichloromethane and stirred at a temperature of −15° C. A solution of chloroacetyl chloride (40 μl, 1 eq.) in 1 ml of dichloromethane (CH2Cl2) was added dropwise to the resulting suspension. The resulting mixture was stirred at room temperature for 2 hours. 20 ml of dichloromethane were then added, and the resulting organic phase was washed with three times 50 ml of 5% hydrochloric acid and then dried over MgSO4, filtered and evaporated. 2-Chloro-1-[4-(3-thiophen-2-yl[1,2,4]oxa-diazol-5-yl)piperid-1-yl]ethanone was obtained in the form of a white solid, in a yield of 95%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:14]#[N:15]>C(Cl)(Cl)(Cl)Cl.[W].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:19][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[O:10][CH3:9]
Reactant: COc1cc(C#N)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C#N)ccc1CBr
Yield: 65 %

Procedure:
N-Bromosuccinimide (3.2 g.) and benzoyl peroxide (0.005 g.) were added to a solution of 3-methoxy-4-methylbenzonitrile (2.65 g.) in dry carbon tetrachloride (90 ml.). The mixture was heated to reflux for 15 minutes using a 250 watt tungsten lamp. The cooled reaction mixture was diluted with petroleum ether (b.p. 60°-80° C., 90 ml.), insoluble material removed by filtration, and the filtrate evaporated. The solid residue was recrystallized from a mixture of dichloromethane and petroleum ether to give 4-bromomethyl-3-methoxybenzonitrile (W) (2.64 g., 65%) as a white solid, m.p. 87°-91° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C@H:10]([O:19][CH3:20])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:20][O:19][C@H:10]([CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[CH2:9][NH2:8]
Reactant: [H][H]
Reactant: CO[C@H](CN1CCN(C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](CN)CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(2S)—N,N-Dibenzyl-2-methoxy-3-(4-methylpiperazin-1-yl)propan-1-amine 38a (500 mg, 1.36 mmol) was dissolved in 20 mL of methanol followed by the addition of palladium/carbon (100 mg, 10%), filled with hydrogen for three times. The reaction mixture was stirred at room temperature for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (2S)-2-methoxy-3-(4-methylpiperazin-1-yl)propan-1-amine 38b (250 mg, as a yellow oil liquid), which was used in the next step without further furification.
Reaction SMILES: [C:1]1([OH:21])[C:2]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH:22]1[CH2:26][CH2:25][CH2:24][CH:23]=1>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W]>[CH:22]1([C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)=[C:1]([OH:21])[C:2]=2[C:11]2[C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Oc1c(-c2ccc3c(c2)CCCC3)ccc2c1CCCC2
Reactant: C1=CCCC1
Agent: [W]
Agent: P
Solvent: O
Product: Oc1c2c(cc(C3CCCC3)c1-c1cc3c(cc1C1CCCC1)CCCC3)CCCC2
Yield: 41.3 %

Procedure:
A mixture of 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binapthol (48 g), phosphotungstic acid (2.4 g) and cyclopentene (58 g) was charged into a Hastelloy reactor. The reactor was heated to 180 C for 40 hours. The mixture was purified by column chromatography (silica gel, eluting with 2% ethyl acetate/hexane) to yield 29.5 g (42%) of 3,3′-dicyclopentyl-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binapthol, mp 143–152° C. 13C NMR (CDCl3): 22.96, 25.31, 26.68, 29.19, 32.72, 32.75, 39.20, 118.58, 128.14, 129.20, 129.74, 133.91, 149.14 ppm. 1H NMR (CDCl3): 1.60 (m, 10H), 2.0 (d, 4H), 2.65 (t, J=4 Hz, 2H), 3.27 (quintet, J=7 Hz, 1H), 4.55 (s, 1H), 6.92 (s, 1H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)(CC)C>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=c1cc(Cl)nc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]cn2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a suspension of 6-chloro-3H-pyrimidin-4-one (˜0.23 mol) in sec-butanol (525 mL) was added ethyldiisopropylamine (49.7 mL, 0.3 mol) and BOC-piperazine (available from Aldrich; 55.9 g, 0.3 mol). The reaction was stirred at 80° C. for 8 hours, and then allowed to cool to room temperature. The crude reaction mixture was filtered, and washed with sec-butanol to give 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester (47.8 g, 74%) LCMS Purity=100% (Rt=1.42). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 5.34 (s, 1H), 3.56-3.46 (m, 4H), 3.46-3.38 (m, 4H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@H:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH3:24])[CH:19]=[N:20][C:21]=3[F:22])[CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[CH:10]=2)=[CH:17][C:18]([C@H:23]([N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)[CH3:24])=[CH:19][N:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNCC4)cnc3F)nc(C)n2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A mixture of tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate (0.57 g, 0.87 mmol) in CH2Cl2 (4.3 mL) at 0° C. was treated with TFA (1.29 mL, 17.36 mmol). The reaction mixture was allowed to warm up to RT. After 90 minutes the reaction mixture was concentrated and the residue was dissolved in CH2Cl2 and saturated NaHCO3 (aq.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 6-(2-fluoro-5-((1R)-1-(1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.41 g, 0.74 mmol, 85% yield). m/z (ESI, +ve) 557.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J=9.29, 2.45 Hz, 1H); 8.14-8.18 (m, 1H); 7.18 (d, J=7.43 Hz, 4H); 6.86 (d, J=8.61Hz, 4H); 6.83 (br. s, 1H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.57 (q, J=6.78 Hz, 1H); 2.96 (m, 4H); 2.62 (s, 3H); 2.57 (br. s., 2H); 2.44-2.51 (m, 2H); 1.40 (d, J=6.85 Hz, 3H).
Reaction SMILES: COC1C=CC2OC=CC=2C=1.[CH2:12]([C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=2[CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[CH2:31]([N:33]([CH2:46][CH3:47])[CH2:34][CH2:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)[CH3:32]>>[CH2:12]([C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=2[C:23]=1[C:41](=[O:42])[C:40]1[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][N:33]([CH2:46][CH3:47])[CH2:31][CH3:32])=[CH:45][CH:44]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2oc(Cc3ccccc3)cc2c1
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Agent: COc1ccc2occc2c1
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccc(OC)cc23)cc1

Procedure:
In like manner, when 5-methoxybenzofuran is used as a starting material in the procedure of Example 34 and the resulting 2-benzyl-5-methoxybenzofuran is acylated with 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride, 2-benzyl-3-[4-(2-diethylaminoethoxy)benzoyl]-5-methoxybenzofuran is obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH2:16])=[O:15]>O1CCOCC1>[C:13]([C:14]1[O:15][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:16]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(C)(C)C(N)=O
Solvent: C1COCCO1
Product: CC(C)(C)c1nc(-c2ccc(F)cc2)co1
Yield: 1254.2 %

Procedure:
Reflux a solution of commercially available 2-bromo-4′-fluoroacetophenone (100.00 g, 460 mmol), 2,2-dimethyl-propionamide (93.06 g, 20 mmol) in 1,4-dioxane (600 mL) for 2 days. Filter precipitate, concentrate filtrate, and purify (silica gel chromatography, eluting with hexanes:EtOAc 60:1) to give the title compound (55 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=CN=C(NNC(OC(Cl)(Cl)Cl)=O)C=2C2C=CC=CC=2)=CC=1.Br[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:61][C:60]([F:62])([F:63])[C:57]1[CH:58]=[CH:59][C:54]([CH2:53][N:15]2[C:14](=[O:17])[N:11]3[CH:12]=[N:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[C:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:55][CH:56]=1
Reactant: O=c1[nH]nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C(NNc1ncnc(-c2ccc(Cl)cc2)c1-c1ccccc1)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 60 °C

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one and/or trichloromethyl 2-(6-(4-chlorophenyl)-5-phenylpyrimidin-4-yl)hydrazinecarboxylate (16.0 mg, 0.05 mmol) in acetone (5 mL) at room temperature under argon was added 1-(bromomethyl)-4-(trifluoromethyl)benzene (23.9 mg, 0.10 mmol), followed by K2CO3 (13.8 mg, 0.10 mmol). The resulting mixture was heated at 60° C. for 24 h. Insoluble material was filtered and rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure and purified by reverse phase preparative HPLC (without TFA). Further purification was performed by silica gel column chromatography eluting with EtOAc-hexanes. Pure product was lyophilized from 1,4-dioxane to obtain the title compound (5.0 mg) as an off-white lyophilate. HPLC/MS: retention time=4.18 min. [M+H]30 =481. 1H NMR (CDCl3): δ 8.70 (s, 1H), 7.65 (d, J=7.3 Hz, 2H), 7.55 (d, J=7.3 Hz, 2H), 7.23-7.46 (m, 7H), 7.20 (d, J=7.2 Hz, 2H), 5.18 (s, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:7]2[CH2:8][CH2:9][C:4]3[CH:3]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[O:1][C:5]=3[CH2:6]2)=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc2c(o1)CNCC2
Reactant: O=C(O)CCCCCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 95 mg (0.52 mmol) of methyl 4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylate, 0.12 g (0.63 mmol) of 6-phenylhexanoic acid and 0.15 ml (1.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.10 ml (0.63 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O-].[Na+].[Na].Cl[CH2:27][C:28]#[N:29]>C(OCC)C.C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:27][C:28]#[N:29])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCc1ccc(O)cc1)OCc1ccccc1
Reactant: N#CCCl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: N#CCOc1ccc(CCNC(=O)OCc2ccccc2)cc1
Reaction time: 5 h

Procedure:
48.82 g. (0.18 mol) of the above-prepared N-(benzyloxycarbonyl)-p-hydroxyphenethylamine are introduced into a sodium ethylate solution freshly prepared from 5.17 g. sodium and 270 ml. ethanol, 11.4 ml. (0.18 mol) chloroacetonitrile are slowly added dropwise thereto and the reaction mixture is heated to the boil. After 5 hours, the solvent is stripped off, the residue is taken up in diethyl ether, extracted twice with 2N aqueous sodium hydroxide solution, washed neutral, dried over anhydrous sodium sulphate and evaporated to dryness. The oily residue is recrystallised from ligroin/diethyl ether (8:2 v/v). There are obtained 44.74 g. (80% of theory) of the desired product in the form of colourless crystals; m.p. 110°-115° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([S:16][CH:17]([CH3:19])[CH3:18])[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.[O:20]1CCOCC1>O>[CH:17]([S:16][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH:1]=[O:20])[CH:15]=1)([CH3:19])[CH3:18]
Reactant: C1COCCO1
Reactant: Cc1cc(SC(C)C)c2ccc3cccnc3c2n1
Solvent: O
Product: CC(C)Sc1cc(C=O)nc2c1ccc1cccnc12
Yield: 41 %

Procedure:
A solution of SeO2 (1.06 g, 9.6 mmol) in a mixture of dioxane (50 mL) and water (2 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 2-methyl-4-isopropylsulfanyl-[1,10]phenanthroline (1.03 g, 3.8 mmol) in hot dioxane (50 mL) was added through an addition funnel over a period of 30 minutes and the reaction mixture was refluxed for 1 hour. The reaction mixture was filtered while hot and the residue rinsed with more hot dioxane (20 mL) and filtered. The filtrates were combined and concentrated in vacuo and the residue was treated with methylene chloride (100 mL) and a 10% K2CO3 aqueous solution (100 mL). The aqueous layer was extracted several times with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (neutral Al2O3, MeOH/DCM, 1:50 to 1:15) to afford the pure product as a light yellow solid (0.44 g, 41%).