Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Cl[C:18]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>C1COCC1>[NH3:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][O:10][C:18]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: COc1ccc(COc2cc(Cl)nc3ccccc23)cc1
Reactant: OCCCNCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(OCCCNCc3ccc(Cl)c(Cl)c3)nc3ccccc23)cc1
Product: N
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
A solution of 3-(3,4-dichlorobenzylamino)propanol (47 mg, 0.2 mmol) in dry THF (0.5 ml) was added to a suspension of sodium hydride (60% dispersion in oil, 8.0 mg, 0.2 mmol) at room temperature under an argon atmosphere. After 10 min the mixture was heater to reflux for a further 20 min. A solution of 2-chloro-4-(4-methoxybenzyloxy)quinoline (62 mg, 0.2 mmol) in dry THF (0.5 ml) was added and reflux continued under an argon atmosphere for a further 30 min. The solvent was evaporated, the residue dissolved in toluene and applied to a column of Kieselgel 60. Elution with a mixture of 70:29:1 ethyl acetate:hexane:2M methanolic ammonia afforded the title compound as a colourless oil (17 mg, 17%); δH (CDCl3) 1.6 (1H, br. s.), 1.97-2.12 (2H, m), 2.79 (2H, t, J=6.8 Hz), 3.76 (2H, s), 3.84 (3H, s), 4.57 (2H, t, J=6.2 Hz), 5.14 (2H, s), 6.27 (2H, s), 6.96 (2H, d, J=8.6 Hz), 7.13-7.44 (6H, m), 7.58 (1H, dt, J=1.1, 7.1 Hz), 7.70 (1H, d, J=8.2 Hz), 8.09 (1H, d, J=8.2 Hz); MS (ES+) 497 (MH+, 50%), 216 (100).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:38][CH2:39][CH3:40])[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[OH:21])[CH3:2].[N:41]1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C(C)C)(C(C)C)C(C)C)(=O)=O.[C:67]([O:70]CC)(=[O:69])C>ClCCl>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:38][CH2:39][CH3:40])[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:41][C:67](=[O:69])[O:70][N:37]=3)=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[OH:21])[CH3:2]
Reactant: CCCc1nc(CC)c(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1cccc(C)n1
Reactant: CCOC(C)=O
Agent: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc(CC)c(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 77 %

Procedure:
To a mixture of 4′-{[4-ethyl-5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (1.5 g) and 2,6-lutidine (0.98 mL) in dichloromethane (10 mL) was added triisopropylsilyl trifluoromethanesulfonate (1.5 mL) at 0° C. After stirring for 2 hr, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in dimethyl sulfoxide (5 mL), and then hydroxylamine hydrochloride (1.7 g) and sodium hydrogen carbonate (2.5 g) were added. The mixture was stirred overnight at 90° C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.6 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added. After stirring for 30 min, the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 77%).
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:1]([N:14]1[CH:19]=[C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccc(C(F)(F)F)cc1
Yield: 43.3 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 14 (Step 2), starting from 1-benzhydryl-5-iodo-pyrimidine-2,4-dione (0.33 g, 0.82 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.23 g, 1.22 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 70:30) to afford the title compound (0.15 g, 45%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 7.27-7.33 (m, 4H), 7.35-7.46 (m, 6H), 7.47 (s, 1H), 7.55-7.63 (m, 2H), 7.65-7.73 (m, 2H), 11.78 (s, 1H). MS (ESI) m/z: 371 [M-H]−. MS (ESI) m/z: 373 [M-H]+, 390 [M-NH4]+.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:22])=[N:17][CH:18]=[C:19](Br)[CH:20]=2)=[CH:11][CH:10]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>O1CCOCC1.C(Cl)(Cl)Cl.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>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([C:27]3[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=3)[CH:20]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.2 %

Procedure:
Water (5 ml), potassium carbonate (1742 mg) and tetrakis(triphenylphosphine)palladium (242 mg) were added to a solution of the compound obtained in Step 1 of Example 1 (1110 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (874 mg) in 1,4-dioxane (50 ml), and the mixture was stirred at 100° C. for five hours. After leaving to cool, the reaction solution was diluted with chloroform. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=96:4 (v/v)] to give 638 mg of the title compound as a solid.
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:33])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][CH:18]=2)[CH:10]=1)=[O:8])=O)C.ClCCl.CO>CO>[CH3:33][S:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][CH:18]=2)[CH:10]=1)(=[NH:6])=[O:8]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc3c(Nc4nccs4)ncnc3c2)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=N)(=O)c1cccc(CNc2ccc3c(Nc4nccs4)ncnc3c2)c1
Yield: 77 %

Procedure:
According to GWP 6, the conversion of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[3-({[4-(thiazol-2-ylamino)quinazolin-7-yl]amino}methyl)phenyl]sulphoximide (40 mg, 0.083 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→20% methanol) gives the desired product in 77% yield (26 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:11]=[N:12][NH:13][N:10]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Cc2nn[nH]n2)cc1
Yield: 46.7 %

Procedure:
4-Bromophenylacetonitrile (30.0 g. 0.15 mol), sodium azide (10.9 g. 0.17 mol) and ammonium chloride (8.9 g. 0.17 mol) were heated in DMF (300 mL) at 90° C. for 2 days. After concentration, water (200 mL) was added to the residue, the mixture was basified with 1M NAOH (170 mL) and washed with ether (2×100 mL). Acidification of the aqueous layer with 1N HCl and collection of the precipitate by suction filtration produced the crude product. This was purified by recrystallization from ethanol to provide 5-[(4-bromophenyl)methyl]-2H-tetrazole (17.2 g, 0.07 mol) in 44% yield, mp. 173°-1750C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: Nc1cccnc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1cncc(Nc2cccnc2)c1
Reaction time: 15 h
Yield: 84.4 %

Procedure:
To a solution of 3-bromopyridine (4.75 gm, 30 mmol) and 3-aminopyridine (1.88 gm, 20 mmol) in dry toluene (8 mL) was added sodium t-butoxide (2.3 gm, 24 mmol), tris(dibenylideneacetone) dipalladium(0) (63 mg, 0.069 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (183 mg, 0.317 mmol). The vessel was capped with a septum, degassed (3×), and heated at 100 C for ˜24 hours. The cooled reaction was diluted with methylene chloride, washed with NaHCO3 solution, water, and the organic layer dried over anhydrous sodium sulfate, filtered and the solvent concentrated to a small volume. Upon addition of diethyl ether and a few drops of methanol the product precipitated. After stirring this mixture for ˜15 hours the purified product was isolated by filtration to give 2.89 gm (84% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]([C:9]1[O:10][C:11]2[C:16]([C:17](=[O:26])[C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[C:13]([Cl:27])[CH:12]=2)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[C:35]1([CH3:44])[CH:40]=[CH:39][C:38]([C:41](Cl)=O)=[CH:37][CH:36]=1>C(Cl)Cl.CCOCC>[CH2:19]([C:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:5]([N:4]1[CH2:3][CH2:2][N:1]=[C:44]1[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)[CH:6]([CH3:7])[CH3:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(NCCN)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C2=NCCN2C(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Yield: 50 %

Procedure:
To a cooled (0° C.) solution of 2-[1-(2-amino-ethylamino)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (4.1 g, 11 mmol) and triethylamine (2.2 mL. 17 mmol) in methylene chloride (100 mL) was added a solution of p-toluoyl chloride (1.7 mmol) in methylene chloride (20 mL). The reaction was maintained at 0° C. for 2 hours, at which time it was diluted with ether (250 mL). The resultant solution was washed with 1 N hydrogen chloride (2×200 mL), saturated sodium bicarbonate (200 mL) and brine (150 mL), dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (0→60% ethyl acetate/hexanes) to give 2.8 g, (50%) of the title compound. MS (ES+) m/e 503 [M+H]+.
Reaction SMILES: C[O-].[Na+].[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[CH3:27][N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>CO>[CH3:27][N:28]1[CH2:29][CH:30]=[C:31]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([NH:13][S:14]([C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][CH:18]=4)(=[O:15])=[O:16])[CH:8]=3)[NH:4][CH:5]=2)[CH2:32][CH2:33]1
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cccc2ccccc12
Reactant: CN1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(NS(=O)(=O)c4cccc5ccccc45)cc23)CC1
Yield: 52 %

Procedure:
To a solution of 712 mg (13.2 mMol) of sodium methoxide in 100 ml of methanol are added 850 mg (2.64 mMol) of N-[1H-indol-5-yl]naphthalene-1-sulphonamide followed by 596 mg (5.28 mMol) of 1-methyl-4-piperidone and the resulting solution is heated to reflux for 48 hours. The reaction mixture is concentrated at reduced pressure and the residue obtained is purified by chromatography over silica gel, using as eluent mixtures of methylene chloride/methanol/ammonia, to yield 573 mg (52%) of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide as a solid with m.p.=244–245° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[CH2:11](N(CC)CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CN(C=O)C>[F:10][C:4]1[CH:3]=[C:2]([CH:20]2[CH2:11][CH:19]2[C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: C=CC(=O)OCC
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Temperature: 110 °C
Reaction time: 21 h

Procedure:
In a 350-mL pressure-tube was added 4-bromo-2,6-difluorophenol (23.82 g, 0.11 mol), triethylamine (55 mL, 0.39 mol), ethyl acrylate (34.27 g, 0.34 mol), DMF (50 mL), palladium (II) acetate (1.29 g, 5.75 mmol), and tri-o-tolyphosphine (2.34 g, 7.6 mmol) under N2. The mixture was sealed in the glass tube and was stirred at 110° C. overnight (21 hours). The reaction was cooled to room temperature and EtOAc (150 mL) was added. The mixture was stirred for 30 minutes, filtered through celite and rinsed with EtOAc (3×100 mL). The filtrate was acidified with 2N HCl to pH ˜2. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and washed with water (2×100 mL), brine (100 mL) and dried over sodium sulfate. After filtration, heptane (200 mL) was added and the solution was concentrated in vacuo. The resulting precipitate was filtered, washed with heptane (50 mL×2) and dried to afford the desired product as a light-yellow solid. The mother liquor was concentrated in vacuo to obtain additional desired product (10) as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.50 (d, J=15.9 Hz, 1H), 7.09 (d, J=8.3 Hz, 2H), 6.29 (d, J=15.9 Hz, 1H), 5.54 (br, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[OH:19][CH2:18][C@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of the compound of Step A (1) ((R)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 6.3 g, 23 mmol) in THF (200 mL) was added triethylamine (36.5 mmol) followed by ethyl chloroformate (27.3 mmol). The mixture was stirred at rt for 2 h. NaBH4 (91.0 mmol) was then added and the mixture was stirred for 10 min. To the resulting mixture was added MeOH (40 ml) very slowly. When the addition was complete, the mixture was stirred for 3 h. The reaction was then concentrated in vacuo and the residue was partitioned between 1N NaOH and ethyl acetate (600 mL). The organic phase was washed with H2O, dried (Na2SO4), and concentrated in vacuo to give 5.5 g (91%) of the title compound: 1H NMR (CDCl3, 500 MHz) δ 1.49 (9H, s), 3.02 (1H, dd, J=5, 15 Hz), 3.50 (2H, brd s), 3.61 (1H, d, J=10 Hz), 4.30 (1H, d, J=15 Hz), 4.44-4.52 (1H, m), 4.67-4.76 (1H, m), 7.09-7.18 (4H, m). MS (ESI) (M+H)+ 264.19.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:28]1[C:33]2[N:34]([CH2:37][C:38]([OH:40])=O)[CH:35]=[N:36][C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26].[NH2:41][CH:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]([CH3:54])([CH3:53])[C:51]#[N:52])=[C:46]([F:55])[CH:45]=1)[CH3:43].CCN(CC)CC>CC#N.O>[C:25]([C:28]1[C:33]2[N:34]([CH2:37][C:38]([NH:41][CH:42]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([C:51]#[N:52])([CH3:54])[CH3:53])=[C:46]([F:55])[CH:45]=3)[CH3:43])=[O:40])[CH:35]=[N:36][C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(F)c1
Reactant: CC(=O)c1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc2ncn(CC(=O)NC(C)c3ccc(C(C)(C)C#N)c(F)c3)c12

Procedure:
2-(7-Acetyl-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-fluorophenyl]ethyl}acetamide is synthesized according to example 5 by mixing HATU (179 mg, 0.472 mmol), 7-acetyl-1H-benzimidazol-1-ylacetic acid (103 mg, 0.472 mmol) prepared according to scheme 4, 2-[4-(1-aminoethyl)-2-fluorophenyl]-2-methylpropanenitrile (97.0 mg, 0.472 mmol) prepared according to scheme 7 and Et3N (143 mg, 1.42 mmol, 0.200 mL) in dry MeCN (10.0 mL). The product is purified by reverse phase HPLC: Gilson prep pumps; Flow rate: 30 ml/min; Column: Gemini (50 21.2×50 mm; Mobile phase: A=10.0 mM NH4HCO3 in H2O B=MeCN (52.4 mg, 0.129 mmol, 27.0%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.36 (d, J=7.03 Hz, 3H) 1.70 (s, 6H) 2.40 (s, 3H) 4.72-4.90 (m, 1H) 5.17 (dd, J=21.48, 17.19 Hz, 2H) 7.18 (d, J=7.81 Hz, 1H) 7.21-7.32 (m, 2H) 7.40 (t, J=8.30 Hz, 1H) 7.72 (d, J=7.62 Hz, 1H) 7.86 (d, J=7.81 Hz, 1H) 8.22 (s, 1H) 8.72 (d, J=7.42 Hz, 1H); MS [M+H] calcd.: 407.18. found: 407.17.
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][OH:11])=[CH:7][CH:6]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[Br:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][O:11][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[CH:7][CH:6]=1
Reactant: C1=COCCC1
Reactant: OCCc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(CCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into 30 mL of CH2Cl2 in a 150 mL RB flask was dissolved 4-bromophenethyl alcohol (7.00 g, 34.80 mmol) and 3,4-dihydro-2H-pyran (3.80 mL, 41.61 mmol). To this solution was added a few crystals of p-toluenesulfonic acid monohydrate. The reaction mixture was then stirred at room temperature under a blanket of nitrogen overnight. Overnight the reaction mixture changed colour again to a deep brown colour. The reaction mixture was transferred to a 250 mL separating funnel and extracted with 150 mL of saturated NaHCO3(aq) solution during which time the brown colouration in the organic layer faded to an orange colour. The layers were separated and the organic layer was extracted again with 150 mL of brine. The organic layer was then separated and dried over anhydrous MgSO4 for 1 hour at room temperature. The mixture was then filtered and the collected solid washed with 3×30 mL portions of CH2Cl2. The filtrate and washings were combined and stripped to dryness on a rotary evaporator to yield an orange oil. Column chromatographic conditions for the remainder of the crude product were determined by TLC analysis (10% EtOAc/90% n-hexane eluant) which indicated a major spot at Rf 0.5 with a few minor spots on and around the baseline. The crude product was then purified by dry column flash chromatography using a sinter of 80 mm diameter and 80 mm depth packed to a depth of 5.5 cm with Merck 60 (15-40 μm) silica gel, time per fraction: 4.00 minutes, crude product pre-loaded onto 12.5 g of Merck 60 (15-40 □m) and this loaded on top of the column. n-Hexane/EtOAc elution in 100 mL fractions with the EtOAc component increasing in 1% increments from 0% (fraction 1) to 15% (fraction 16). Fractions' 9 & 10 “foamed” on leaving the column and TLC (10% EtOAc/90% n-hexane) of fractions' 8-15 indicated pure product was contained in fractions' 9-12 and these were combined and stripped to dryness on a rotary evaporator before being further dried in vacuo (oil immersion pump) overnight at room temperature. Yield: 9.821 g (98.9%, colourless liquid). 1H NMR (CDCl3) δ 1.40-1.88 (m, 6H, [3×—CH2—]pyran), 2.86 (t, 2H, ArCH2—), 3.45 (m, 1H, [OCHaHb-]pyran), 3.58 (q, 1H, —OpyranCHaHb—), 3.73 (m, 1H, [OCHaHb-]pyran), 3.92 (q, 1H, —OpyranCHaHb—), 4.57 (m, 1H, [—OCHO-]pyran), 7.10 (d, 2H, ArH), 7.40 (d, 2H, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].[CH2:19]([Li])CCC.CCCCCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]([CH3:17])[CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH3:19])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14]
Reactant: [Li]CCCC
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-bromo-6-isopropyl-4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-quinoline (Intermediate 5, 6.81 g, 24.9 mmol), and 150 ml of anhydrous THF under argon at −78° C. was slowly added 1.6 M solution of n-butyl lithium and hexane (33 ml, 52.4 mmol). The reaction mixture was stirred at −78° C. for 10 minutes and thereafter N,N-cirmethylformamide (8.0 ml, 100 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 15 minutes and then quenched with saturated NH4Cl. The product was extracted with diethyl ether. The organic layer was washed with water and brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (silica, using 5% ethyl acetate in hexane) to give the title compound as a yellow oil.
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]=[CH2:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC>[C:7]1([CH:6]([OH:13])[CH2:4][CH:3]=[CH2:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CCBr
Reactant: O=Cc1ccccc1
Agent: [Mg]
Solvent: CCCCCC
Product: C=CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The following procedure for the preparation of allylpinacolboronate ester is representative. A 25-mL round-bottom flask equipped with a magnetic stir bar was charged with magnesium turnings (0.04 g, 1.65 mmol) and fitted with a rubber septum. The flask was purged with argon and charged with dry THF (2.3 mL) followed by PinBH (0.199 mL, 1.37 mmol). To the reaction mixture allylbromide (0.116 mL, 1.37 mmol) was added drop wise with constant stirring over five minutes at 25° C. After stirring for 30 min at 25° C., a second equivalent of allylbromide (0.116 mL, 1.37 mmol) was added. After 90 min of stirring at 25° C. the magnesium turnings were fully consumed and 11B NMR analysis confirmed the complete formation of allylpinacolboronate. Benzaldehyde (0.138 mL, 1.37 mmol) was then added and the reaction mixture was stirred for addition 12 h at 25° C. The reaction mixture was then diluted with hexane (5 mL), quenched with aqueous 1 M HCl (5 mL) and transferred to a separatory funnel. The organic layer was washed with aqueous 1 M NaOH (2×5 mL) and DI water (2×3 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and dried under vacuo (25° C., 1 Torr) to afford 1-phenyl-3-buten-1-ol as a clear colorless oil; 94.5% (0.190 g). The results for the other allylpinacolborane esters prepared by this method are summarized in Table 3.