Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH3:2]>CO.CCOC(C)=O.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(/C=C/c2ccccc2)cc1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(Cc1ccc(CCc2ccccc2)cc1)S(C)(=O)=O
Reaction time: 20 h
Yield: 99.5 %

Procedure:
A solution of trans-7-[methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acid ethyl ester (0.60 g) in MeOH (5 mL) and EtOAc (50 mL) was added to 10% Pd/carbon (0.2 g). The reaction mixture was placed on a Parr hydrogenator and was hydrogenated for 20 h at 50 psi. The reaction mixture was filtered through celite and concentrated in vacuo to afford 7-[methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic acid ethyl ester (0.60 g). 1H NMR (400 MHz, CDCl3) δ7.30-7.10 (m, 9H), 4.32 (s, 2H), 4.10 (q, 2H), 3.12 (t, 2H), 2.90 (s, 4H), 2.79 (s, 3H), 2.25 (t, 2H), 1.60-1.45 (m, 4H), 1.30-1.19 (m, 7H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:4].[CH3:13][C:14]([CH3:16])=[O:15]>O>[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:13][C:14](=[O:15])[CH3:16])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(C)=O
Reactant: CCc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C=CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 ml of 10% strength sodium hydroxide solution is added to a mixture of 111.4 (0.83 mol) of 4-ethylbenzaldehyde, 133 g of acetone and 100 ml of water, and the mixture is stirred overnight at room temperature. It is then diluted with 300 ml of ice water and extracted five times, each time with 100 ml of dichloromethane. The extracts are dried over sodium sulfate and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]#N)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C(O)=[O:27]>O=[Pt]=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[O:27])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: O=CO
Agent: O=[Pt]=O
Product: Cc1cc(C=O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (400.0 mg, 1.16 mmol) and PtO2 (26.0 mg, 0.115 mmol) were added to formic acid (2 mL) and the mixture was heated at 60° C. for three hours. The NMR spectrum showed 40% conversion, so PtO2 (50.0 mg) was added to the mixture and it was allowed to stir at 60° C. overnight. After cooling, the mixture was filtered through Celite® and concentrated. Column chromatography (30% EtOAc/Hexanes) provided the title compound as a white solid (357.5 mg, 88%). 1H NMR (300 MHz, CDCl3): δ 10.08 (s, 1H), 7.71 (s, 2H), 7.35 (d, 3H), 7.19 (d, 3H), 4.80 (s, 2H), 4.32 (s, 2H), 2.83 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=2[CH3:29])=[CH:19][CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccn(C)c(=O)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (20 mg, 0.04 mmol) in ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (0.5 mL) at room temperature. The mixture was heated to 40-45° C. and stirred for 3 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (10 mL). The aqueous solution was washed with diethyl ether (25 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 17 mg (89% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C23H20Cl2N2O4 (M+Na) 481.0691. found 481.0699.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH2:11]([CH2:13][NH2:14])[OH:12].C(=O)(O)[O-].[Na+]>C(#N)C>[OH:12][CH2:11][CH2:13][NH:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: NCCO
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cccc(CNCCO)c1
Reaction time: 4 h
Yield: 44.5 %

Procedure:
3-(Bromomethyl)benzonitrile (20.0 g, 0.125 mol) was added portion wise into a mixture of ethanolamine (11.4 g, 0.19 mol) and sodium bicarbonate (21.0 g, 0.25 mol) in ACN (200 mL) at 0° C. The resulting mixture was stirred for 4 hours. The reaction mixture was concentrated under vacuum. The residue was taken up with water and extracted with DCM (200 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to afford the title compound as white solid (9.8 g, 54%). 1H NMR (DMSO-d6, 400 MHz) δ 7.76 (s, 1H), 7.67 (m, 2H), 7.51 (m, 1H), 4.47 (brs, 1H), 3.74 (s, 2H), 3.44 (m, 2H), 2.51 (m, 2H), 2.12 (brs, 1H).
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[NH:14][C:13]1=[O:20])=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[NH:14][C:13]1=[O:20]
Reactant: [H][H]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1N

Procedure:
(3S,4S)-3-benzyloxycarbonylamino-4-acetoxy-azetidin-2-one (2.00 g, 7.188 mmole) was hydrogenated with 2 g of 10% palladium on activated carbon in ethyl acetate (50 ml) at 50 psi hydrogen pressure at room temperature for 1.5 hrs. After removal of catalyst by filtration, the deproteced (3S,4S)-3-amino-4-acetoxy-azetidin-2-one in ethyl acetate was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[C:12]([C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH2:29][CH3:30])=[C:22]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[N:21]=1)(=O)[NH2:13]>O>[NH2:13][CH2:12][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH2:29][CH3:30])=[C:22]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[N:21]=1
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N3CCC[C@@H]3C(N)=O)nc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(N3CCC[C@@H]3CN)nc21
Temperature: 0 °C

Procedure:
A suspension of 56 mg (1.47 mmol) of LiAlH4 in 2 ml of abs. THF is added to a suspension of 150 mg of 2-[(R)-(−)-2-carbamoyl-pyrrolidin-1-yl]-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine (cf. Example 45) in 10 ml of abs. THF and the mixture is stirred at 80° C. for 22 h. After further addition of 56 mg of LiAlH4, the mixture is allowed to react further for 18 h. 5 ml of WATER are then added dropwise, with ice/water cooling, and the reaction mixture is then poured onto 50 ml of ice/water. The mixture is extracted three times with ethyl acetate. The combined organic extracts are washed twice with water and once with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure. The resulting crude product (oil) is purified by means of column chromatography and digestion in diisopropyl ether. 2-[(R)-2-Aminomethyl-pyrrolidin-1-yl]-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine is obtained; m.p. 126–129° C.; FAB-MS: (M+H)+=372, HPLC: tret (grad20/2)=11.09 minutes.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:19])[CH:13]=[CH:14][C:15]=2[CH2:16]OC)[N:9]=1)[NH2:3].[N:20]#[C:21][NH2:22].C(OCC)C>CO>[NH2:19][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[C:15]([CH:16]=[N:22][C:21]#[N:20])=[CH:14][CH:13]=1
Reactant: N#CN
Reactant: COCc1ccc(=N)[nH]c1-c1csc(N=C(N)N)n1
Solvent: CCOCC
Solvent: CO
Product: N#CN=Cc1ccc(N)nc1-c1csc(N=C(N)N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (4.0 g) and cyanamide (1.2 g) in methanol (80 ml) was stirred for 16 hours at ambient temperature. To the mixture was added a diethyl ether (80 ml) and isolated precipitate was collected by filtration. The precipitate was added to a mixture of ethyl acetate and water and adjusted to pH 9.5 with 20% aqueous potassium carbonate. The precipitate was collected by filtration and recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-[6-(amino)(cyanoimino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (3.04 g).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)(=[O:12])=[O:11])(=[O:3])[CH3:2].N1C=CN=C1.[Si:28](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C=C[NH+]=CC=1.Br[Br-]Br.[BH4-].[Na+]>C1COCC1.O.CN(C=O)C>[Cl:9][C:7]1[S:6][C:5]2[S:10](=[O:12])(=[O:11])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=3)[CH2:2][CH:1]([OH:3])[C:4]=2[CH:8]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1cc(Cl)sc1S(=O)(=O)Nc1ccc(CCO)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCc1ccc(N2CC(O)c3cc(Cl)sc3S2(=O)=O)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
The product from Step B (11.5 g, 0.032 mol) was added to DMF (100 mL) containing imidazole (5.44 g, 0.08 mol) and t-butyldiphenylsilyl chloride (9.34 mL, 0.035 mol) and stirred at room temperature for 18 hr. The reaction mixture was evaporated to dryness and the residue was suspended in methylene chloride and filtered. The filtrate was concentrated and chromatographed (silica, methylene chloride) to provide a solid which was dissolved in THF (200 mL) and cooled to 5° C. A solution of pyridinium bromide perbromide (11.23 g, 0.035 mol) in THF (50 mL) was added dropwise and this mixture was stirred at 5° C. for 1 hr, at ambient temperature for 1 hr, and then evaporated to dryness. The residue was suspended in ethanol (150 mL) and cooled to 5° C. followed by the addition of sodium borohydride (3.59 g, 95 mmol). The reaction mixture was maintained at room temperature for 1 hr and then heated at reflux temperature for 1.5 hr. Water was carefully added and the ethanol evaporated. The aqueous mixture was neutralized and extracted with ethyl acetate (2×200 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 15% ethyl acetate/hexane) to provide an amber syrup (8.2 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14].[Cl:20][S:21](O)(=[O:23])=[O:22]>>[Cl:20][S:21]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([CH3:14])[N:5]([CH2:4][C:3]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=3[Cl:1])[C:9]=2[CH:10]=1)(=[O:23])=[O:22]
Reactant: Cc1nc2ccccc2n1Cc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)Cl
Product: Cc1nc2ccc(S(=O)(=O)Cl)cc2n1Cc1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In an ice bath, 1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (4.00 g) is added to chlorosulfonic acid (20 ml) and the solution is stirred for 24 hours at room temperature and at 1.5 hours at 80° C. The reaction solution is poured into ice water, precipitated gummy solids are separated through filtration, and thus, a mixture of 5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole is obtained. This material is immediately used for the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]([F:48])([F:47])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:36]2[CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=[C:34]([C:33]([F:32])([F:48])[F:47])[CH:35]=2)[CH:12]=[C:13]([O:15][S:16]([C:19]([F:21])([F:22])[F:20])(=[O:18])=[O:17])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 26, step (c)) under the conditions described in Example 26, step (d-f)) using 3,5-bis-trifluoromethylphenylboronic acid in step (d).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[OH2:7]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[O:7]=[CH:4][C@@H:2]([C@H:1]([C@@H:4]([C@@H:2]([CH2:1][OH:6])[OH:3])[OH:7])[OH:6])[OH:3]
Reactant: O
Agent: CC(O)C(=O)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Of such biodegradable plastics, PLA (poly lactic acid) is a polymer of the low molecular compound (monomer), called lactic acid, present in the living organisms, and has been known that it is converted into the low molecular compound by hydrolysis with water and then, decomposed with microbes. Poly lactic acid fibers are prepared according to the process which comprises fermenting corn starch to produce lactic acid via glucose and then condensing lactic acid to prepare PLA, which is then subjected to melt spinning or melt molding procedure together with polyesters or nylons. Corn is composed of starch, gluten, husk, hull and fiber, and germ, with starch accounting for 65%, which is converted into lactic acid through fermentation. In this case, the optical isomer in which L-form of lactic acid constitutes the main part and D-form is also present is produced. Cargill Inc. in USA has developed the raw material of PLA (NatureWorks PLA) and supplied under the trademark “Ingeo”. Also, three to four Japanese companies and Novament of Intaly have also developed and practically implemented PLA materials. It has been known that PLA has the molecular structure of H—(OCH(CH3)CO)n-OH and the melting point of about 175° C. Therefore, it dose not burn at high temperature of the process for manufacturing the vegetation basis of the present invention and remains in the artificial soil to keep the framework of the basis. Although general corn starch fibers can also be used, the sheath-core type corn starch fibers were also marketed and therefore, such commercialized product can be purchased and used. They can be prepared so that the sheath component has a low-melting point (e.g. 130-140° C.) and the core component has a high-melting point (e.g. 160-170° C.). The sheath-core type corn starch fibers provides the effects identical to those of using said sheath-core type polyester fibers, and thus, forms sufficient pores in the artificial soil and also allows the soil structure to have a strong solidarity.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1O.CI.O>CN(C)C=O>[Br:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:4][CH3:1]
Reactant: CS(=O)(=O)c1ccc(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(C)(=O)=O)cc1Br
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Potassium carbonate (2.31 g, 16.8 mmol) was added to a solution of 2-bromo-4-(methanesulfonyl)phenol (Description 27; 3.5 g, 14 mmol) in dimethylformamide (50 ml). The resulting solution was stirred for 30 min. and methyl iodide (1.04 ml, 16.8 mmol). After stirring for 1 h. the solution was poured into water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined organics were washed with water and dried over sodium sulphate. Removal of the solvent in vacuo gave a white solid which was crystallised from diethyl ether to give the title compound (2.02 g). 1H NMR (250 MHz, CDCl3) δ8.12-8.11 (1H, d, J 2.2 Hz), 7.90-7.86 (1H, dd, J 8.7, 2.2 Hz), 7.04-7.00 (1H, d, J 8.7 Hz), and 3.99 (3H, s), and 3.05 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH3:37])[N:3]=1.Cl>C(OCC)(=O)C.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15](=[O:25])[CH2:16][NH2:17])=[CH:26][CH:27]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH3:37])[N:3]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)CNC(=O)OC(C)(C)C)cc2)nc(N)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)CN)cc2)nc(N)n1
Reaction time: 16 h
Yield: 48 %

Procedure:
A solution of tert-butoxycarbonylamino-acetic acid 4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl ester in ethyl acetate (15 ml) was treated with a solution of hydrogen chloride in dioxane (4.0 M, 15 ml). After stirring for 16 hours, the solid was filtered and dried under reduced pressure to provide the hydrochloride salt of the title compound (0.273 g, 48% yield). 1H NMR (DMSO-d6) δ 1.39 (t, 3H, J=6.4 Hz, CH3), 3.89 (d, 2H, J=4.9 Hz, CH2), 4.17 (q, 2H, J=6.2 Hz, CH2), 5.25 (s, 2H, CH2), 6.70 (s, 1H, Ar), 7.28 (d, 1H, J=8.7 Hz, Ar), 7.46 (d, 2H, J=8.4 Hz, Ar), 7.62-7.67 (m, 2H, Ar), 7.88 (d, 2H, J=7.4 Hz, Ar), 8.37 (s, 3H), 11.10 (s, 1H), 12.68 (s, 1H).
Reaction SMILES: [CH:1]1([N:7]([CH2:15][CH:16]([OH:18])[CH3:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:21]=1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:21]=1[C:22]([O:18][CH:16]([CH3:17])[CH2:15][N:7]([C:8]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:14])[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:23]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CC(O)CN(C(=O)OC(C)(C)C)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(=O)OC(C)CN(C(=O)OC(C)(C)C)C2CCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl cyclohexyl(2-hydroxypropyl)carbamate (1 g, 3.89 mmol) in dry toluene (10 ml), 2,4,6-trimethyl-benzoyl chloride (0.510 mL, 4.280 mmol) was added. The resultant reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulphate, and concentrated to dryness to obtain 1-((tert-butoxycarbonyl)(cyclohexyl)amino)propan-2-yl 2,4,6-trimethylbenzoate. Yield: 1 g (64.10%); LCMS: m/z=404.4 [M+H], RT=2.76 min, (Column: Y, Program: P1)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1

Procedure:
A round bottom flask was charged with 4-bromobenzoic acid (2.0 g, 9.95 mmol) in chloroform (150 mL). To the solution was added thionyl chloride (3 mL) in chloroform (10 mL), 2-3 drops of dimethylformamide (DMF). The slurry was heated at reflux for 3 hr. while monitoring the reaction through a bubbler. A clear solution of 4-bromobenzoyl chloride was obtained, the volatiles were removed and a light yellow oil was obtained which solidified upon cooling.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>[Cu]I>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Product: Brc1ccc2c3ccccc3n(-c3ccccn3)c2c1
Temperature: 90 °C
Yield: 70 %

Procedure:
Under a nitrogen atmosphere, 10 mmol of 2-bromo-9H-carbazole, 15 mmol of 2-bromopyridine, 1 mmol of copper(I)iodide, 25 mmol of potassium carbonate, and 2 mmol of L-proline were combined in stirring degassed dimethyl sulfoxide. The mixture was heated to 90° C. for 3 days before being cooled and separated between dichloromethane and water. The water layer was washed twice with dichloromethane and the organics were combined and washed once with brine. The organic fraction was dried with magnesium sulfate and concentrated under reduced pressure and subjected to column chromatography of silica with dichloromethane as the eluent. After concentrating under reduced pressure, 2-bromo-9-(pyridin-2-yl)-9H-carbazole was isolated in a 70% yield.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]2[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC1CN(Cc2ccccc2)CCO1

Procedure:
A mixture of 31.8 g of 2-chloromethyl-4-benzylmorpholine and 30.5 g of potassium phthalimide in 200 ml of dimethylformamide is refluxed for 4 hours and then poured into water. The precipitated crystals are collected by filtration and dried to give 40.2 g of 2-phthalimidomethyl-4-benzylmorpholine. To 400 ml of the ethanol solution of this product is added dropwise a solution of 12.3 g of hydrazine hydrate in 100 ml of ethanol. Further, the resultant mixture is refluxed for 30 minutes. After cooling, insoluble materials are filtered off and the filtrate is concentrated under reduced pressure to give 2-aminomethyl-4-benzylmorpholine as an oily substance. To the solution of 10.3 g of the obtained product in 400 ml of ethanol and 40 ml of water are added 11 g of concentrated hydrochloric acid and 1.1 g of 10% palladium-carbon and the mixture subjected to catalytic reduction at ordinary temperature and atmospheric pressure. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue is treated with ethanol-acetone to give 2-(aminomethyl)morpholine dihydrochloride as white crystals, melting at 215°-218° C.