Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:22]([NH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:24])[CH3:23]
Reactant: NCC1CN(Cc2ccccc2)CCO1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of crude 2-aminomethyl-4-benzylmorpholine (48 g) in toluene (400 ml) was added pyridine (24.5 ml, 0.303 mol) and then acetic anhydride (26.4 ml, 0.280 mol) was added dropwise under ice-cooling over 10 minutes and then allowed to rise to room temperature and the mixture was stirred for one hour. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate (200 ml) under ice-cooling and then 10% aqueous sodium hydroxide was added until the mixture became strongly basic. The reaction mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layer was washed with aqueous saturated sodium chloride (200 ml). The organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1/1) to give 2-(N-acetylaminomethyl)-4-benzylmorpholine (25.93 g). A total yield of 3 steps=56%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>C(O)C>[CH3:18][CH2:17][O:16][C:14]([C:13]1[CH:7]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]#[N:12])[C:6]2[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]=1[NH2:12])=[O:15]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1cc(Br)ccc1O
Solvent: CCO
Product: CCOC(=O)C1=C(N)Oc2ccc(Br)cc2C1C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
To a suspension of the 5-bromosalicylaldehyde (0.010 mol) in dry ethyl alcohol (30 ml) was added ethyl cyanoacetate (0.022 mol) and 3.0 grams of molecular sieve 3Å powder (Aldrich Chemical Company). The resulting mixture was stirred at room temperature overnight (14 h). Most of the 5-bromosalicylaldehyde disappeared within the first 2 hours as layer chromatography (TLC). The molecular sieve was then filtered off and washed 3 times with tetrahydrofuran. The filtrates were combined and the solvent was removed under vacuum. The residue solidified when incubated at −24° for 2 hours. The desired product was obtained by crystallization in 85% ethanol as a single diastereoisomeric pair. The yield was 86%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.N1C=CC=CC=1.Cl>O>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1
Reactant: NCCCN
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: NCCCNc1ccc(Br)cn1

Procedure:
A mixture of 1,3-diaminopropane (17.6 ml), 2,5-dibromopyridine (10 g) and pyridine (5 ml) was heated under reflux for 4 hr. After stripping off the excess of 1,3-diaminopropane, the residue was taken up in water, the pH adjusted to 7 (conc. hydrochloric acid) and the solution extracted with chloroform. The pH was raised to 14 and extracted with chloroform. After drying (K2CO3), the final extract was evaporated to give 2-(3-aminopropylamino)-5-bromopyridine (9.1 g) as an oil which was used without further purification. (ii) To a suspension of sodium hydride (0.3 g) in DMSO (20 ml) was added 2-(3-aminopropylamino)-5-bromopyridine (2.88 g). The mixture was stirred and heated slowly to 85° C. After the evolution of hydrogen had ceased the mixture was cooled to room temperature and methyl iodide (1.77 g) in DMSO (5 ml) added dropwise maintaining the temperature below 30° C. After a further 15 min water (150 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with water and extracted with 1N hydrochloric acid. The acid extract was washed with chloroform, the pH adjusted to 13 (2N NaOH) and extracted again with chloroform. The final extract was stripped and the residue chromatographed (silica gel, 5% ammoniacal methanol/dichloromethane) to give 2-[N-(3-aminopropyl)-N-methylamino]-5-bromopyridine (1.44 g) as an oil which was used without further purification. (iii) 2-[N-(3-aminopropyl)-N-methylamino]-5-bromopyridine (1.4 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.25 g) were heated together under reflux in pyridine (10 ml) for 20 hr. After stripping, the residue was triturated with wet ether and recrystallised from isopropanol/water to give 2-[3-[N-methyl-N-(5-bromopyrimid-2-yl)amino]propylamino]-5-(6-methylpyrid-3-yl-methyl)pyrimid-4-one, 1.5 g (71%) mp 137°-40° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Mg]Br.C(OCC)C>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)[C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:10]([OH:11])[CH3:27])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1c(C=O)cc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1c(-c2ccc(C(F)(F)F)nc2)cc(C(C)(C)C)cc1C(C)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (1.0 g, 2.72 mmol) in THF (15 mL) at −78° C. under argon was added a 3 M solution of methyl magnesium bromide in diethyl ether (1.0 mL, 3.0 mmol). The reaction mixture was stirred at −78° C. for 10 minutes and then the solution poured onto brine cooled to 0° C. forming a gel. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase was separated, dried (Na2SO4), filtered, and the solvent removed under reduced pressure to give 1-(5-(tert-butyl)-2-(methoxymethoxy)-3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)ethan-1-ol (660 mg, 63% yield) as a tan oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:25]([C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:31])([F:15])[F:32])[O:21][N:20]=4)[CH:23]=3)=[O:26])[CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: COc1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: COc1ccc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)nc1
Yield: 36 %

Procedure:
This compound was synthesized from 1-(5-methoxypyridin-2-yl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (60 mg, yield 36%). 1H NMR (400 MHz, MeOD) δ 8.28-8.25 (m, 1H), 8.21-8.20 (m, 1H), 7.87-7.86 (m, 1H), 7.74-7.72 (m, 2H), 7.32-7.29 (dd, J=9.2 Hz, 3.1 Hz, 1H), 6.89-6.86 (d, J=9.3 Hz, 1H), 3.93 (m, 2H), 3.80 (s, 3H), 3.62 (m, 2H), 3.55 (m, 2H), 3.43 (m, 2H). MS (ESI) m/z: Calculated for C20H18F3N6O3: 433.14. found: 434.0 (M+H)+
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[C:17]1([CH2:23][CH2:24][C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)CCc1ccccc1
Product: O=C(CCc1ccccc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 3-phenylpropanoic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.46 (m, 1H), 8.15 (td, J=7.7, 1.4 Hz, 1H), 7.99-8.09 (m, 2H), 7.28-7.34 (m, 4H), 7.20-7.25 (m, 1H), 2.94 (t, J=7.7 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H); MS (ESI−) M/Z 360 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9](Br)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:13]1([Sn](C)(C)C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Li+]>CN(C)C=O.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)c1ccccc1
Reactant: CCOC(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1
Temperature: 100 °C
Yield: 46 %

Procedure:
A mixture of 2-bromopyridine-5-carboxylic acid ethyl ester (see part (i)) (1.855 g, 8.065 mmol), phenyltrimethyl tin (3.89 g, 16.13 mmol), bis(triphenylphosphine)palladium(II) chloride (371 mg) and lithium chloride (1.03 g. 24. 195 mmol) in dry dimethylformamide (40 ml) was heated at 100° C. for 1.5 hours under nitrogen. After cooling the mixture was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (10:1, by volume) to give the title compound (0.843 g, 46%) as a white solid.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28].[BH3-]C#N.[Na+]>CCO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15](=[CH:14][CH:13]=2)[CH:16]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH:18]=[CH:19]3)[CH2:9][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)NC(=O)CCN
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)NS(C)(=O)=O)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N-(methylsulfonyl)propanamide (239 mg, 1.19 mmol, 1.5 equiv) were dissolved in anhydrous EtOH. The mixture was stirred at 80° C. for 1 h. Then NaBH3CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80° C. for 16 h. The organic layer was concentrated and purified by prep-TLC to give 3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(methylsulfonyl)propanamide as a white solid (62 mg, 14%). (mobile phase: CH3OH/DCM=1:10). ESI-MS (M+1)+: 461.2, HPLC: 96.38%. 1H NMR (400 MHz, DMSO-d6) δ: 7.93 (s, 1H), 7.85˜7.77 (m, 2H), 7.59˜7.49 (m, 1H), 7.43˜7.35 (m, 1H), 7.20˜7.11 (m, 1H), 4.45˜4.33 (m, 1H), 4.20 (s, 2H), 2.98 (t, 2H), 2.77 (s, 3H), 2.35 (t, 2H), 2.26˜2.14 (m, 2H), 1.86˜1.75 (m, 2H), 1.41˜1.30 (m, 2H), 1.27˜1.14 (m, 2H), 1.13˜1.02 (m, 1H), 0.89 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:9])[CH3:8].Br[Mg][C:12]#[CH:13]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])([C:12]#[CH:13])[CH3:8]
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1ccccn1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(pyridin-2-yl)ethan-1-one (6.0 g, 49.53 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of bromo(ethynyl)magnesium (0.5 M in THF, 250 mL, 2.50 equiv) dropwise with stiffing at 0° C. The resulting solution was stirred for 30 min at 0° C. The resulting solution was allowed to react, with stirring, for an additional 18 h at room temperature. The reaction was then quenched by the addition of 50 mL of saturated aqueous NH4Cl. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/hexane (1/10). This resulted in 0.8 g (11%) of 2-(pyridin-2-yl)but-3-yn-2-ol as a off-white solid. 1H-NMR (300 MHz, CDCl3, ppm) δ: 8.534 (d, 1H), 7.800-7.744 (t, 1H), 7.620 (d, 1H), 7.295-7.263 (m, 1H), 5.481-5.300 (br s, 1H), 2.546 (s, 1H), 1.797 (s, 3H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=1>CN(C)C=O.Cl>[CH3:34][O:33][C:22]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[O:28])=[CH:25][CH:24]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 16 h

Procedure:
4.93 g (26.5 mmol) of t-butyl piperazine-1-carboxylate and 4.8 ml (34.5 mmol) of triethylamine were stirred in 50 ml of dimethylformamide under cooling with ice. 5.25 g (26.5 mmol) of monomethyl terephthalate chloride was slowly added to the resultant mixture, and they were stirred for 16 hours. The temperature was elevated to room temperature, and the reaction liquid was diluted with 1 N hydrochloric acid. After the extraction with ethyl acetate followed by the treatment in an ordinary manner, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([N:28]=[C:29]=[O:30])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:29]([NH:28][C:20]3[CH:19]=[C:18]([O:17][CH3:16])[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=3)=[O:30])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Product: COc1cc(NC(=O)Nc2cc(Nc3cccc(Cl)c3)ncn2)cc(OC)c1OC

Procedure:
The title compound is prepared analogously as described in Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 3,4,5-trimethoxyphenyl isocyanate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([CH3:24])[C:14]([O:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=3)[O:11][CH:10]=2)=[CH:7][C:6]=1[O:27][CH3:28])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH:9]2[CH:18]([OH:19])[C:17]3[C:12](=[C:13]([CH3:24])[C:14]([O:20][C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=3)[O:11][CH2:10]2)=[CH:7][C:6]=1[O:27][CH3:28])(=[O:3])[CH3:2]
Reactant: COc1cc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)ccc1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2COc3c(ccc(OC(C)=O)c3C)C2O)ccc1OC(C)=O

Procedure:
4′,7-Diacetoxy-3′-methoxy-8-methylisoflavan-4-ol was prepared from 4′,7-diacetoxy-3′-methoxy-8-methylisoflavone (0.25 g, 0.7 mmol) in methanol (50 ml) using palladium-on-charcoal (5%, 0.07 g) by the method described above.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:34][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[C:7]=2[C:6]=1[CH3:35])=[O:4].Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:34][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:35])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCN(C(=O)OC(C)(C)C)C3)c2c1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCNC3)c2c1C
Reaction time: 8 h

Procedure:
To a stirred suspension of 4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (1.2 g) in MeOH (4.0 ml) was added HCl in dioxane (4N; 4.0 ml) dropwise. The reaction mixture was stirred for 8 h. The solvent was removed under reduced pressure. The residue was purified by chromatography.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH:25]=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)C.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH2:25][CH2:24][C:22]1[CH:21]=[CH:20][N:19]2[C:15]([C:13]([NH:12][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]4[C:11]=3[C:3]([CH3:1])=[N:4][N:5]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:14])=[CH:16][N:17]=[C:18]2[CH:23]=1
Reactant: COCCN
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Product: COCCNCCc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1

Procedure:
Prepared according to procedure for Example 72 from N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide and 2-methoxyethanamine. MS (ES+APCI) m/z=498 (M+H) detected.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][N:7]=[C:6]2[NH:14][CH:15]([CH3:17])[CH3:16].CN(C)C=O>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[OH:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][CH:15]([CH3:17])[CH3:16])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:2]=[O:1]
Reactant: CC(C)Nc1ncnc2cc(O)c(CO)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)Nc1ncnc2cc(O)c(C=O)cc12
Yield: 56 %

Procedure:
6-(Hydroxymethyl)-4-(isopropylamino)quinazoline-7-ol (510 mg, 2.19 mmol) is dissolved in 50 mL of toluene and 5 mL of dimethylformamide and at room temperature admixed portionwise with manganese(IV) oxide (1.9 g, 21.9 mmol). After 24 hours the batch is filtered through Celite and washed with dichloro-methane/methanol 9/1. Removal of the solvent and also chromatographic purification (silica gel, dichloromethane/methanol: 0→50% methanol) gives the desired product in 56% yield (280 mg).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][N:5]=1>N1C=CC=CC=1>[NH:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][N:5]=1)[NH2:2]
Reactant: COCCOc1ccnc(Cl)c1
Reactant: NN
Solvent: c1ccncc1
Product: COCCOc1ccnc(NN)c1
Yield: 32.8 %

Procedure:
Hydrazine (10 mL, 318.6 mmol) was added to a solution of 2-chloro-4-(2-methoxyethoxy)pyridine (1.00 g, 5.330 mmol) in pyridine (25 mL), then heated to reflux. After 18 hours the reaction mixture was partitioned between H2O and DCM and the aqueous phase was extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (40:1 DCM/MeOH followed by 20:1 DCM/MeOH) to provide 320 mg (33%) of desired product as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:27](=[O:28])[CH2:26][NH:25][C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:24]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
L-proline methylester hydrochloride (13.6 g, 82.7 m mole) was suspended in chloroform (200 ml) and to the suspended solution triethylamine (8.3 g, 82.7 m mole) was added while cooling. To the solution, N-t-butyloxycarbonyl glycine (14.5 g, 82.7 m mole) was added and WSC hydrochloride (15.82 g, 82.7 m mole) was gradually added thereto while cooling with ice. The reaction was carried out for 2 hours while cooling with ice, and next overnight at room temperature. The reaction solution was washed with 10% citric acid, aqueous sodium chloride, 5% sodium bicarbonate and aqueous sodium chloride in order, and dried with anhydrous sodium sulfate. The solution was distilled under reduced pressure leaving a syrupy N-t-butyloxycarbonylglycyl-L-proline methylester product (22.5 g, 78.5 m mole, yield: 95%). This product gave a single spot with Rf =0.48 by silica gel thin layer chromatography (developing solvent, benzene:ethyl acetate=1:1, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrin and heating).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.CO.[NH3:20]>>[NH2:20][CH2:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)[OH:9]
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Reactant: N
Solvent: CO
Product: NCC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Temperature: 130 °C

Procedure:
2-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-oxirane (500 mg, 1.40 mmol) was dissolved in 2M NH3 in methanol (5 ml, 10.0 mmol) and the solution was heated in a microwave at 130° C. for 60 minutes. Upon cooling, the solvent was removed in vacuo to furnish the desired product. Three identical reactions were carried out and afforded 1.55 g (98%) of the product 2-amino-1-(4-chloro-phenyl)-1-[4-iodo-phenyl]-ethanol. The crude product was pure and was used in the next step without purification.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH2:10][C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH:1]1([C:7]([NH:9][CH:10]([C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CNC(=O)C1CCCCC1)c1ccco1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)C1CCCCC1)C(=O)c1ccco1
Yield: 56.3 %

Procedure:
6.5 g of N-cyclohexylcarbonyl-(2-furylcarbonyl)methylamine, 1.3 g of 61% sodium hydride and 5.1 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 5.0 g ethyl 3-cyclohexylcarbonylamino-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 56.2%
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[CH2:14][C@:13]4([CH:19]5[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]5)[CH2:15]4)[O:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[Br:22]Br>CN(C=O)C.C(Cl)(Cl)Cl>[Br:22][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]1[CH:7]=[C:8]2[CH2:14][C@:13]3([CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[O:12][C:9]2=[N:10][CH:11]=1
Reactant: c1cc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)co1
Reactant: BrBr
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Brc1occc1-c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
(2′R)-5′-(Furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (102 mg, 0.37 mmol), was stirred with bromine (65 mg, 0.41 mmol) in DMF (3 ml) at room temperature for 1 h. Vaccum was applied, and the mixture was stirred for a further 30 min. The reaction mixture was diluted with chloroform, and washed with aqueous sodium hydroxide, then the organic layer was dried, filtered and evaporated. The compound was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound (28 mg) as a pale solid; m/z 361, 363 (MH+).