Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][O:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 120.3 %

Procedure:
In a round-bottomed flask, (cis-3-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (500 mg, 2.21 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. and triethylamine (0.40 ml, 2.87 mmol) was added followed by methanesulfonyl chloride (0.20 ml, 2.57 mmol). The reaction mixture was stirred at 0° C. for 45 min then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 780 mg of methanesulfonic acid (cis)-3-tert-butoxycarbonylamino-cyclopentylmethyl ester as a pale yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:16]=O)=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2.O.[OH-].[Na+].Cl.[CH3:22][C:23]([CH3:25])=[O:24]>>[Cl:1][C:2]1[C:3]([CH:16]=[CH:22][C:23](=[O:24])[CH3:25])=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2
Reactant: CC(C)=O
Reactant: CCC1(C)Cc2c(C)c(C)c(C=O)c(Cl)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(C)Cc2c(C)c(C)c(C=CC(C)=O)c(Cl)c2C1
Yield: 73.7 %

Procedure:
To a solution of 14.7 g of the 7-chloro-2-ethyl-2,4,5-trimethylindan-6-carboxaldehyde in 45 ml of absolute acetone was added 22 ml of water and 24 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified with 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 12.65 g of the title compound as brown oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:31]=[CH:30][C:22]4[O:23]C(C)(C)[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[ClH:42]>CCO.O>[ClH:42].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:31]=[CH:30][C:22]([OH:23])=[C:21]([CH:20]=3)[C:26]([OH:27])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)O)c1
Yield: 65 %

Procedure:
To a solution of 6-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (240 mg, 8.4 mmol) in EtOH (15 mL) and water (1 mL) was added an aqueous solution of NaOH (0.5 mL, 5N). The reaction mixture was heated under reflux for 2 hrs. Then an aqueous solution of HCl (2 mL, 5N) was added and the solvents were evaporated under reduced pressure to give a brown oil. The oil was taken up with water (10 mL) and extracted with Et2O (2×10 mL). The combined organic layers were dried over MgSO4 and the volume of solvent was half reduced under reduced pressure. Then a solution of HCl in Et2O (2 mL, 1M) was added and a beige solid precipitated out. The solid was filtrated off, washed with Et2O and dried under vacuum to give 155 mg (65%) of the title compound as a beige powder. HPLC, Rt: 4.7 min (purity: 99.7%). LC/MS, M−(ESI): 482.3. 1H NMR (CD3OD) δ: 7.87 (d, J=3.0 Hz, 1H), 7.61 (dd, J=9.0, 3.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.13 (d, J=9.0 Hz, 1H), 4.82 (s, 2H), 3.77 (t, J=8.1 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.63 (m, 4H), 1.45-1.33 (m, 8H), 0.96 (m, 6H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:29][CH:26]4[CH2:28][CH2:27]4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: NC1CC1
Solvent: C1COCCO1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NC4CC4)nc32)c(=O)[nH]c1=O
Temperature: 100 °C

Procedure:
A mixture of the product from example 44 step (viii) (0.25 g) and cyclopropylamine (0.44 ml) in dry 1,4-dioxane (3 ml) was heated at 100° C. for 34 h. The solvent was removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic extracts were dried (MgSO4) and evaporated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>CC(O)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:29]/[N+:26]([O-:28])=[O:27])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a solution of 4-(4-Chloro-3-(trifluoromethyl)phenoxy)benzaldehyde (13 g, 43.2 mmol) and ammonium acetate (1.67 g, 21.62 mmol) in HOAc (40 mL), was added nitromethane (6.99 mL, 130 mmol). The reaction mixture was stirred at 120° C. for 5 h, and concentrated. The residue was dissolved in DCM (150 mL), washed with sat. aqueous NaHCO3 (100 mL×2), brine and then, dried over anhydrous Na2SO4 and concentrated to afford the title compound as a brown solid (14.3 g, 63% yield).
Reaction SMILES: [F:1][CH:2]([F:36])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20]CC3C=CC(OC)=C(OC)C=3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[F:36][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH2:20])[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1
Reactant: COc1ccc(CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(3,4-dimethoxy benzyl)-6-(morpholin-4-yl)pyrimidin-2-amine (5.3 g) and trifluoroacetic acid (0.82 mL) was stirred at 10 for 1 hour. The reaction mixture was neutralized by the addition of saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and washed with diisopropyl ether to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-amine (1.36 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[CH:34]=[CH:33][N:32]=[CH:31]4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M49) (0.15 g, 0.29 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (55 mg, 47%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:16][CH2:17][CH2:18][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCBr)c1
Yield: 76 %

Procedure:
To a stirred solution of diethyl 1H-pyrrole-2,4-dicarboxylate (0.7 g, 3.31 mmol), and 1,2-dibromoethane (2.8 mL, 32.5 mmol) in MeCN (30 mL) was added K2CO3 (0.55 g, 39.7 mmol). This reaction mixture was refluxed overnight then filtered. The filtrate was collected and concentrated to give diethyl 1-(2-bromoethyl)-1H-pyrrole-2,4-dicarboxylate (0.8 g, 76%). 1H NMR (CDCl3, 300 MHz) δ7.42 (d, J=1.8 Hz, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 4.60 (t, J=6.0 Hz, 2 H), 4.22 (q, J=7.2 Hz, 4 H), 3.62 (t, J=6.4 Hz, 2 H), 1.28 (m, 6 H).
Reaction SMILES: [F:1][CH:2]([F:24])[CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5]C(=O)OCC1C=CC=CC=1.[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27]>[Pd].CO.C(Cl)Cl>[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].[NH2:5][CH2:4][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:2]([F:24])[F:1]
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(F)F
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of benzyl tert-butyl (3,3-difluoropropane-1,2-diyl)biscarbamate (195 g, 567 mmol) and palladium on carbon (10% w/w, 20 g) in methanol (2000 mL) was stirred at room temperature under a hydrogen atmosphere. After 16 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with DCM (2500 mL) and oxalic acid (2.84 M solution in methanol, 200 mL, 567 mmol). After 2 hours, the mixture was filtered, and the collected solids were washed with DCM (500 mL) and dried in an oven under reduced pressure to afford tert-butyl (3-amino-1,1-difluoropropan-2-yl)carbamate oxalic acid salt. MS ESI calc'd. for C8H17F2N2O2 [M+H]+ 211. found 211. 1H NMR (400 MHz, D2O) δ 6.14-5.86 (m, 1H), 4.25 (d, J=12.8 Hz, 1H), 3.36 (d, J=14 Hz, 1H), 3.11-3.05 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[CH3:38][O:39][C:40]1[CH:49]=[CH:48][C:43]2B(O)[O:45][CH2:46][C:42]=2[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[OH:45][CH2:46][C:42]1[CH:41]=[C:40]([O:39][CH3:38])[CH:49]=[CH:48][C:43]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)=[O:29]
Reactant: COc1ccc2c(c1)COB2O
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
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: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)c(CO)c1
Yield: 99.9 %

Procedure:
Dissolve trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (300 mg, 0.56 mmol), 5-methoxy-3H-benzo[c][1,2]oxaborol-1-ol(275 mg, 1.7 mmol) and 2M sodium carbonate (0.5 mL, 13 mmol) in dimethoxyethane (5.0 mL). Degas the solution with nitrogen for 15 min. Add tetrakis(triphenylphosphine)palladium (130 mg, 0.11 mmol) and heat at 60° C. for 2 hours. Cool reaction to room temperature and purify on a SCX column to yield 294 mg (100%) of the title compound as a pale yellow foam. 1H NMR (CDCl3) 7.84 (d, J=8.4 Hz, 1H), 7.67 (m, 2H), 7.48 (m, 1H), 7.39 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 7.03 (bs, 1H), 6.82 (m, 2H), 6.57 (m, 1H), 4.44 (m, 1H), 4.28 (bs, 1H), 4.15 (bs, 2H), 3.94 (s, 3H) 3.78 (s, 3H), 2.81 (bs, 2H), 2.52 (bs, 4H) 1.61 (m, 4H), 1.44 (bs, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([CH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:26]=1)#[N:20]>CCO>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:21]([C:22]2[S:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:26]=2)[C:19]#[N:20])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CCc1nc(C(F)(F)F)cs1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(=Cc1ccc(OCc2ccccc2)cc1)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
NaH (516 mg, 60% dispersion in mineral oil, 12.9 mmole) was reacted with absolute EtOH (10 mL) at 0° C. After gas evolution had ceased the mixture was warmed to RT. 4-Benzyloxybenzaldehyde (2.05 g, 9.68 mmole) was added all at once as a solid. To this mixture was added dropwise a solution of 2-cyanomethyl-4(trifluoromethyl)thiazole (1.24 g) in absolute EtOH (20 mL). The reaction was stirred for 4 hr, then the solid was collected by filtration and washed with hexanes to give the title compound (1.64 g, 42% over 2 steps) as a yellow solid: 1H NMR (300 MHz. CDCl3) δ 8.25 (s, 1 H), 8.00 (d, J=6 Hz, 2 H), 7.79(s, 1 H), 7.40 (m, 5 H), 7.10(d, J=6 Hz, 2 H), 5.18 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].O1CCOCC1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]=[C:21]([C:20]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)[NH:8]2
Reactant: Nc1ncnc(Cl)c1N
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1COCCO1
Product: Clc1ccc(-c2nc3c(Cl)ncnc3[nH]2)cc1
Temperature: 100 °C

Procedure:
To a solution of 6-Chloro-4,5-diaminopyrimidine (1 g, 0.007 mol) (Example 89, step a) in 1,4-Dioxane (60 mL, 0.8 mol) was added 4-Chlorobenzaldehyde (2.2 g, 0.016 mol) and Ferric chloride (2.5 g, 0.015 mol) mixed with 28.6 g silica gel, and the mixture was heated at 100° C. for 20 hours. The reaction was cooled to 23° C., filtered and washed with 10% ethanol/ethyl acetate and concentrated. The residue was dissolved in ethyl acetate and washed with water, brine, and concentrated. The residue was triturated in diethyl ether to obtain 272 mg (10%). LC/MS: Rt=1.54 min, ES+ 265 (AA standard).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[F:26])#[N:16]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([F:26])[CH:19]=1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: N#Cc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F
Yield: 35 %

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (4-cyano-3-fluorophenyl)boronic acid on a 0.1 mmol scale. The residue was washed with water (3×5 mL), EtOAc (3×2 mL), and DCM (3×2 mL) and dried under high vacuum to afford 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluorobenzonitrile (T747) as a orange solid (10 mg, 35%). 1H NMR (400 MHz, DMSO-d6): δ 9.74 (d, J=6.8 Hz, 1H), 8.46 (d, J=10.8 Hz, 1H), 8.41-8.38 (m, 2H), 8.19 (t, J=7.6 Hz, 1H), 7.98 (d, J=6.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.45 (t, J=7.2 Hz, 1H); MS (ESI) m/z [M+H]+289.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]2[CH2:10][CH2:11][C@:12]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])([CH3:14])[O:13][C:4]=2[C:3]=1[CH3:31].[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CCCCCC>[CH3:31][C:3]1[C:4]2[O:13][C@@:12]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:24])[CH3:19])([CH3:14])[CH2:11][CH2:10][C:5]=2[C:6]([CH3:9])=[C:7]([O:8][C:32]([CH3:33])=[O:34])[C:2]=1[CH3:1]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude α-tocopherol is treated with 25.0 g of acetic anhydride (corresponding to 244.9 mmol), 25.0 g of pyridine (corresponding to 316.1 mmol) and 1.0 g of 4-dimethyl-aminopyridine (corresponding to 8.2 mmol; catalytic amount) and stirred for one hour at room temperature. The reaction mixture is poured on to 100 g of ice/water (about 1:1), stirred for 30 minutes, treated with 250 ml of n-hexane and washed in succession twice with 150 ml of water each time, twice with 100 ml of 2N sulphuric acid each time, with 150 ml of water, with 150 ml of saturated sodium bicarbonate solution and three times with 150 ml of water each time. Thereafter, the mixture is dried over 3 g of anhydrous magnesium sulphate for 10 minutes while stirring. After filtration, distillation of the solvent at 400 mbar and a bath temperature of 60° C. and subsequent drying for 30 minutes at 15 mbar and a bath temperature of 70° C. there are obtained 29.26 g of α-tocopherol acetate as a yellow oil, α-tocopherol acetate content (GC, internal standard squalane) 87.5%, chemical yield (α-tocopherol acetate) 93.1%. This crude acetate is distilled in a bulb tube oven (250° C./10-1 mbar). There are obtained 26.25 g of α-tocopherol acetate as a slightly yellowish oil which crystallizes slowly upon standing at room temperature. α-Tocopherol acetate content (GC, internal standard squalane) 96.2%, chemical yield 91.8%; stereo-chemical purity: 99.6% R,R,R-α isomer (HPLC of the methyl ether derivative on Chiracel OD, n-hexane); the product is identical with α-tocopheryl acetate according to 1H-NMR, IR, MS and microanalytical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2I)=[CH:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:18])[C:9]=2[CH:20]=[CH2:21])=[CH:4][CH:3]=1
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2ccccc2c1-c1ccc(Cl)cc1
Yield: 89.2 %

Procedure:
A solution of 1-(4-chlorophenyl)-2-iodo-3-methylnaphthalene (3E) (1.50 g, 3.98 mmol), tributyl(vinyl)tin (1.28 mL, 4.37 mmol) and PdCl2(PPh3)2 (0.279 g, 0.398 mmol) in DMF (20 mL) was stirred at 90° C. under argon overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with 5% LiCl solution (2×), brine and dried (MgSO4). The mixture was filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 3F as a white solid (0.9894 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.74 (d, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.40-7.13 (m, 5H), 7.15 (d, J=8.1 Hz, 2H), 6.50 (dd, J=18, 11.7 Hz, 1H), 5.27 (d, J=11.7 Hz, 1H), 5.03 (d, J=18 Hz, 1H), 2.50 (s, 3 H).
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[C:14](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[C:16]([NH2:19])=[N:17][CH:18]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:12][C:13]1[C:14]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH2:11][CH2:10]2)=[C:15]([N+:20]([O-:22])=[O:21])[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: C1CC(CN2CCNCC2)C1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(CC3CCC3)CC2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 17 h
Yield: 45 %

Procedure:
The resulting 1-(cyclobutylmethyl)piperazine (supposedly 0.086 g, 0.56 mmol, 1 eq) was suspended in iPrOH (0.55 mL) and DIPEA (0.22 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.14 g, 0.56 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL), and dried to give the title compound as a bright yellow powder (0.093 g, 45%); 1H-NMR (500 MHz, DMSO-d6): δ 1.73-1.92 (m, 2H), 1.96-2.05 (m, 2H), 2.37 (d, J=7.0 Hz, 2H, piperazine N(CH2)2), 2.41-2.54 (m, 5H), 3.02 (m, 4H), 6.95 (s, 2H, NH2), 8.15 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.02 min—370/372 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:43]=2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])O1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:12]([NH:11][C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:43]=2)=[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[CH:4]=1)=[O:10])[CH3:13]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(Br)cn1
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)OCC)c2)cn1
Temperature: 100 °C
Yield: 100.6 %

Procedure:
N-[5-bromo-4-(4-phenyl-1,3-thiazol-2-yl)pyridin-2-yl]-N′-ethylurea (Intermediate 69, 0.17 g, 0.42 mmol), ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.14 g, 0.51 mmol), tetrakis triphenyl phosphine palladium (0.024 g, 0.02 mmol), and cesium carbonate (0.165 g, 0.51 mmol) were combined in a microwave vial and degassed with nitrogen. 1,4-dioxane:water (4:1, 2.5 mL) was added to the mixture and the reaction mixture was heated to 100° C. for 60 minutes. The reaction mixture was partitioned between water and ethyl acetate and the layers separated. The organic layer was washed with saturated NaHCO3, water, and brine, then dried over magnesium sulfate. The organic layer was concentrated to form a precipitate, and the resulting solids were filtered and then washed with acetonitrile followed by chloroform to yield 200 mg of the title compound as an off-white solid. LC/MS (ES+)[(M+H)+]: 474 for C25H23N5O3S. 1H NMR (300 MHz, CHCl3): 1.28 (t, 3H), 1.39 (t, 3H), 3.44-3.49 (m, 2H), 4.41 (q, 2H), 7.31-7.39 (m, 2H), 7.52 (s, 1H), 7.62 (d, 2H), 8.17 (s, 1H), 8.28 (t, 1H), 8.32 (t, 1H), 8.4 (s, 1H), 8.71 (d, 1H), 8.73 (d, 1H), 9.23 (d, 1H), 9.27 (s, 1H).