Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18]Br)=[CH:13][C:12]=1[F:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:13][C:12]=1[F:20]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Fc1cc(CBr)c(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Fc1cc(COc2ccc(Cl)c(Cl)c2)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 110.3 %

Procedure:
A mixture of 3,4 dichlorophenol (730 mg, 4.48 mmol), 1-bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene (Preparation 2, 1.35 g, 4.48 mmol), and potassium carbonate (1.87 g, 13.5 mmol) in acetone (56 mL) was stirred for 72 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through Arbocel™. The Arbocel™ was washed with ethyl acetate (2×50 mL) and the combined organic extracts were concentrated in vacuo to afford a pale yellow solid. The solid was then dissolved in ethyl acetate (150 mL) and washed successively with aqueous sodium hydroxide solution (0.5 M, 100 mL), brine (3×100 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford an off white solid (1.90 g). Recrystallisation from hot heptane afforded the title compound (920 mg, 53%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]3[C:16](=[O:17])[C:15]([C:18]([O:20]CC)=[O:19])=[CH:14][N:13]=[C:10]32)=[CH:5][CH:4]=1>C(O)(=O)C.Cl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]=[C:10]32)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2c3cc(OC)ccc3ccn2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ccn3c(=O)c(C(=O)O)cnc3c2c1
Yield: 96 %

Procedure:
A solution of ethyl 10-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (3.0 g., 0.010 mole) in a mixture of acetic acid (45 ml.) and 37% hydrochloric acid (23 ml.) was refluxed for 45 minutes. The mixture was cooled, diluted with water, and the yellow solid collected and dried to give the title acid: 2.6 g.(96% yield) m.p. 261°-263°. Recrystallization from acetic acid followed by n-butyl acetate gave the analytical sample, m.p. 262°-264°.
Reaction SMILES: [O-2].[Sr+2:2].[N+]([O-])([O-])=O.[Sr+2].[N+]([O-])([O-])=O.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1COCC1.N1C=CC=CC=1>[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].[Sr+2:2].[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [O-2]
Agent: [Sr+2]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)[O-]
Reaction time: 12 h

Procedure:
0.103 Gram (1×10-3 mole) of strontium oxide (prepared by the thermal decomposition of strontium (II) nitrate) was taken in a 100 ml round bottom flask. A solution of 0.280 g of methacrylic acid (3.2×10-3 mole) in 1.1 g of THF was added to it. The sytem was kept for stirring for 12 hrs. The slurry so obtained is soluble in pyridine on sonication.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].Cl.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>O>[N+:15]([C:10]1[C:9]([O:12][CH3:13])=[CH:8][C:4]([CH2:5][CH2:6][NH2:7])=[C:3]([O:2][CH3:1])[CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OC)c(CCN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OC)cc1CCN
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
45.5 g (250 mmol) 2,5-dimethoxyphenethylamine J1 was mixed with 40 ml water and cooled to 0° C. while 30 ml conc. HCl was added slowly. The resultant milky emulsion was cooled to 0 to 5° C., and 65 ml conc. HNO3 was added slowly and carefully within about 2 hours, keeping the temperature below 10° C. The mixture solidified when about half of the HNO3 had been added. 50 ml icy water was added to render the mixture stirrable. Then the rest of the HNO3 was added. The mixture was warmed up to room temperature and stirred at room temperature for 3 hours, was basified with 40% NaOH to pH>12 and then extracted with 2×11 CHCl3. The CHCl3 extraction was back washed with 3×110.5 M NaOH and dried over 15 g K2CO3. The solvent was evaporated to afford 49.8 g orange oil (yield: 88%), which crystallized when cooled.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]=[C:13]1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.O.NN>C(O)C>[NH2:3][CH:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]=[C:13]1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N)C1
Yield: 21.7 %

Procedure:
To an ethanol solution (5.0 mL) of tert-butyl 5-(1,3-dioxoisoindolin-2-yl)-4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (500 mg, 2.36 mmol) synthesized in Reference Synthesis Example 201, hydrazine monohydrate (177 mg, 7.08 mmol) was added and the resultant mixture was stirred under reflux by heating for 5 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. Chloroform was added to the obtained residue and the resultant mixture was filtered again, followed by concentrating the resultant filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (150 mg, yield 22%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][CH:10]1[NH:12][CH2:11]1>CCCCCCCCCC>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:9][CH:10]([NH2:12])[CH3:11]
Reactant: Cc1cccc(O)c1
Reactant: CC1CN1
Solvent: CCCCCCCCCC
Product: Cc1cccc(OCC(C)N)c1
Yield: 57.5 %

Procedure:
21.6 Grams (0.20 mol) of m-cresol and 2.3 g (0.04 mol) of propyleneimine in 20 ml of n-decane were allowed to react in an autoclave at 5 kg/cm2G at 150° C. for 6 hours. Thereafter, the resultant reaction product was treated in the same manner as in Example 17 to give 3.8 g of 1-(3-methylphenoxy)-2-propylamine. Its yield was as high as 57%.
Reaction SMILES: C([O:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)C=C.Cl.CN(C)[C:33]1[CH:38]=CC=C[CH:34]=1>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])[CH2:15][CH2:16]2)=[O:10])=[CH:28][C:29]=1[CH2:38][CH:33]=[CH2:34]
Reactant: C=CCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: CN(C)c1ccccc1
Agent: Cl
Product: C=CCc1cc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)ccc1O

Procedure:
1-[1-(4-Allyloxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1.15 g) is dissolved in N,N-dimethylaniline (5 ml) and the mixture is heated at 180°-190° C. for 8 hours. After cooling, the reaction mixture is adjusted to around pH 4 by adding hydrochloric acid thereto. The mixture is extracted with dichloromethane and dried with magnesium sulfate. The solvent is distilled off and the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=3:1→1:3) and further purified by silica gel column chromatography (solvent: dichloromethane:methanol=100:1) and recrystallized from dichloromethane/n-hexane to give 1-[1-(4-hydroxy-3-allylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.22 g) as white powder, m.p.: 87°-90° C.
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[N+:6]([CH3:9])([O-:8])=[O:7].[O-]CC.[Na+].O>C(O)C>[N+:6]([CH2:9][C:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1)([O-:8])=[O:7]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of cyclobutanone (10.0 g, 143 mmol) and nitromethane (12 mL) in ethanol (10 mL) was added sodium ethoxide in ethanol (2.67 M, 2.7 mL, 7.2 mmol). The mixture was stirred for 6 days at room temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The organic phases were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The volatiles were removed by distillation under vacuum to provide 8.51 g of 1-(nitromethyl)cyclobutanol as a yellow liquid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].S(=O)(=O)(O)O.O>C(#N)C>[C:18]([O:17][C:6]1[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.50 kg (6.35 mol) of 2,6-di-tert-butyl-4-methoxyphenol and 658 mL (6.98 mol) of acetic anhydride dissolved in 1.2 L of acetonitrile, 3 mL of conc. sulfuric acid was added and the mixture was stirred overnight at room temperature. To the mixture, a great excess of water was added and the resulting solids were filtered and dried. The obtained 4-acetoxy-3,5-di-tert-butylanisole was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:17][CH:18]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:17][CH:18]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)OC(C)OC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CCCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl butanoate (700 mg, 2.6 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 10 (200 mg, 28% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.89-0.97 (m, 5H), 1.22-1.36 (br. m, 3H), 1.42 (d, J=5.6 Hz, 3H), 1.51-1.60 (m, 2H), 1.72-1.73 (br. m, 2H), 1.90-1.93 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.29 (t, J=6.8 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 6.69 (q, J=5.6 Hz, 1H), 7.48 (t, J=6.0 Hz, 1H), 12.03 (br. s, 1H). MS (ESI) m/z 338.15 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][CH:14]([NH2:16])[CH3:15].Cl.Cl.C[Si](C)(C)CCOC[N:25]1[C:29]2[N:30]=[CH:31][N:32]=[C:33]([C:34]3[CH:35]=[N:36][N:37]([C:39]4([CH2:43][C:44]#[N:45])[CH2:42][NH:41][CH2:40]4)[CH:38]=3)[C:28]=2[CH:27]=[CH:26]1>>[C:44]([CH2:43][C:39]1([N:37]2[CH:38]=[C:34]([C:33]3[C:28]4[CH:27]=[CH:26][NH:25][C:29]=4[N:30]=[CH:31][N:32]=3)[CH:35]=[N:36]2)[CH2:42][N:41]([C:2]2[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:16][CH:14]([CH3:15])[CH3:13])=[O:8])=[C:4]([F:12])[CH:3]=2)[CH2:40]1)#[N:45]
Reactant: CC(C)N
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Product: CC(C)NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 3, Step 1-3 starting from 4-chloro-2,5-difluorobenzoic acid (Aldrich: Cat. #443824), 2-propanamine and {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride. LCMS (M+H)+: m/z=477.2. 1H NMR (400 MHz, DMSO-d6): δ 12.61 (s, 1H), 9.08 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 7.80 (m, 2H), 7.37 (dd, J=13.0, 7.0 Hz, 1H), 7.23 (m, 1H), 6.63 (dd, J=13.0, 8.0 Hz, 1H), 4.51 (d, J=9.0 Hz, 2H), 4.42 (d, J=9.0 Hz, 2H), 3.78 (s, 2H), 4.03 (m, 1H), 1.13 (d, J=6.5 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CSC.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C@H:18]([OH:20])[CH3:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@@H](O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 55.4 %

Procedure:
To a cooled solution, −78° C., of 1-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)ethanone (Example 42, 52 mg, 0.176 mmol) in toluene was added (R)-(+)-2-methyl-CBS-oxazaborolidine (97 mg, 0.352 mmol) followed by BH3.DMS (2 M in THF, 0.176 mL, 0.352 mmol). The reaction was warmed to −20° C. and stirred for 3 h followed by treatment with MeOH. The resulting mixture was warmed to ambient temperature and sat. NaHCO3 (aq.) solution was added. The aqueous layer was extracted with EtOAc and the combined organic fractions were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a white solid (29 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=2.3 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.61 (dd, J=5.5, 8.6 Hz, 2H), 7.51 (d, J=2.3 Hz, 1H), 7.33 (dd, J=2.5, 8.8 Hz, 1H), 7.28 (t, J=9.0 Hz, 2H), 5.44 (d, J=4.3 Hz, 1H), 5.29 (s, 2H), 5.01-4.91 (m, 1H), 1.47 (d, J=6.7 Hz, 3H). [M+H]=298.2.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:20]1[CH2:19][CH2:18][N:17]([C:5]2[N:4]=[C:3]([N:2]([CH3:1])[CH3:23])[CH:8]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)[N:6]=2)[CH2:22][CH2:21]1
Reactant: COc1ccccc1CCl
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CN1CCN(c2nc(Nc3ccc(C)cc3)cc(N(C)C)n2)CC1
Temperature: 200 °C
Yield: 26.9 %

Procedure:
A mixture of N4,N4-dimethyl-N6-(4-methylphenyl)-2-(1-piperazinyl)-4,6-pyrimidinediamine (30 mg, 0.086 mmol), 1-(chloromethyl)-2-methoxybenzene (17 mg, 0.1 mmol) and triethylamine (200 mg, 2 mmol) in 1 DMF (1 mL) heated by microwave at 200° C. for 12 minutes. The crude product was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (10 mg, 27%).
Reaction SMILES: Cl.[Br:2][C:3]1[C:8]2[N:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]([C@@H:12]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH3:13])=[N:11][C:7]=2[CH:6]=[CH:5][C:4]=1[F:36]>O1CCOCC1.CO>[Br:2][C:3]1[C:8]2[N:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:10]([C@@H:12]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)[CH3:13])=[N:11][C:7]=2[CH:6]=[CH:5][C:4]=1[F:36]
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
4N HCl in dioxane (0.5 mL) was added to a solution of [(S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (128 mg, 0.24 mmol) in MeOH (3 mL) and the mixture stirred at RT for 30 min. The volatiles were removed in vacuo and the resulting residue purified by HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90% 0.1% HCO2H in acetonitrile/water) to afford 178 (88 mg, 81%). LCMS (Method K): RT 3.82 min [M+H]+ 451.9/453.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.19-7.86 (3H, m), 7.70 (1H, dd, J=8.75, 4.59 Hz), 7.64-7.33 (5H, m), 7.26 (1H, t, J=9.22 Hz), 5.22 (1H, s), 1.56 (3H, d, J=6.87 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[NH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(COC)OC>C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.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>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[NH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=3)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Brc1ccnc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccnc(OCc4ccccc4)c3)cc2)[nH]1
Temperature: 85 °C
Yield: 96.5 %

Procedure:
A mixture of 2-Benzyloxy-4-bromo-pyridine (0.292 g), 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.533 g, prepared according to WO2008021927 A2) and Pd(PPh3)4 (0.064 g) in aq. K2CO3 solution/dimethoxyethane (1.82 mL/5.0 mL) was heated at 80-90° C. for 8 hours. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 2-{5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.530 g): LCMS-ESI+: calc'd for C30H33N4O3: 497.6 (M+H+). Found: 497.0 (M+H+).
Reaction SMILES: C[CH:2]([CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])C)[CH:3]=O.CC(C(C)(C)C)C[CH2:14][CH:15]=[O:16].CC(C)(C)CCCCC=[O:28]>>[C:15]([OH:16])(=[O:28])[CH2:14][CH2:3][CH2:2][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:10]
Reactant: CC(C=O)CCC(C)(C)C
Reactant: CC(C)(C)CCCCC=O
Reactant: CC(CCC=O)C(C)(C)C
Product: CC(C)CCCCCC(=O)O

Procedure:
Diisobutene, either prepared by the oligomerization of pure isobutene obtained by redissociation or obtained in the course of workup of a butadiene-free raffinate I, is then converted to a C9 derivative lengthened by one carbon atom. Industrial operation involves the hydroformylation or oxo process in which diisobutene is converted to the corresponding aldehyde with carbon monoxide and hydrogen in the presence of rhodium or cobalt catalysts. Since diisobutene predominantly comprises the octenes 2,4,4-trimethyl-1-pentene and 2,4,4-trimethyl-2-pentene, the hydroformylation reaction gives the C9 aldehyde 3,5,5-trimethylhexanal as the main constituent. Further C9 isomers present in small amounts are 3,4,4- and 3,4,5-trimethylhexanal, and also 2,5,5-trimethylhexanal, 4,5,5-trimethylhexanal and 6,6-dimethylheptanal. Oxidation of this aldehyde mixture gives an industrially available isononanoic acid typically having a content of 3,5,5-trimethylhexanoic acid of about 90% (Ullmanns Encyklopädie der technischen Chemie, 4th Edition, 1975, Verlag Chemie, Volume 9, pages 143-145; EP 1 854 778 A1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][C:7](CN)=[N:8][CH:9]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].[CH3:17][N:18](C=O)C>>[Br:3][C:4]1[CH:9]=[N:8][C:7]([N:18]([CH3:17])[S:13]([CH3:12])(=[O:15])=[O:14])=[N:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: NCc1ncc(Br)cn1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CN(c1ncc(Br)cn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.22 g, 60% in oil) was added to a solution of (5-bromopyrimidin-2-yl)methylamine (0.85 g) in DMF (10 ml) at 0° C. and stirred for 30 min. Methanesulphonyl chloride (0.62 g) was added dropwise, the mixture warmed to RT and stirred for a further 2 h. The reaction was quenched with water and then extracted with EtOAc. The organics were washed with water, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 1% methanol/DCM. Yield 0.42 g
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[C@@H:12]1([N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14]>CC(C)=O>[OH:19][CH2:18][CH:17]1[CH:15]2[O:16][C:1]([CH3:6])([CH3:2])[O:14][CH:13]2[CH:12]([N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])[O:20]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: CC(C)=O
Product: CC1(C)OC2C(CO)OC(n3ccc(=O)[nH]c3=O)C2O1
Reaction time: 4 h
Yield: 84 %

Procedure:
Para-toluene sulfonic acid (2.33 g, 12.3 mmoles, 3 eq.) was added to Uridine (1 g, 4.1 mmoles) in 180 mL of anhydrous acetone. After 4 hours at room temperature, acetone was evaporated and the residual crude product was dissolved in 200 mL of ethyl acetate. The organic phase was washed three times with 20 mL of a hydrogenocarbonate 10% solution, then dried over sodium sulfate. The solvent was removed under vacuum. 0.979 g of white powder was isolated (Yield: 83%). The characterization data were consistent with the chemical structure and formula.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][N:13](C)[CH2:14]C2C=CC=CC=2)=[CH:3][CH:2]=1.[H][H].[ClH:36].Cl.CC(O)C>CO.[Pd]>[ClH:36].[ClH:36].[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][C:4]([CH:7]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:3][CH:2]=1
Reactant: CN(CCNCCC(c1ccccc1)c1ccc(-c2ccccc2)cc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CNCCNCCC(c1ccccc1)c1ccc(-c2ccccc2)cc1

Procedure:
A mixture of (±)-N-[3-([1,1′-biphenyl]-4-yl)-3-phenylpropyl]-N′-methyl-N′-(phenylmethyl)-1,2-ethanediamine (0.006 mol) in methanol (150 ml) was hydrogenated at room temperature with palladium on carbon (10%, 1 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, giving a residue that was converted into the hydrochloric acid salt (1:2) with HCl/2-propanol, yielding 2.76 g of (±)-N-[3-([1,1′-biphenyl]-4-yl)-3-phenylpropyl]-N′-methyl-1,2-ethanediamine dihydrochloride (comp. 56).