Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:12]([OH:13])[C@@H:11]([CH2:14][OH:15])[O:10][C@@H:7]([O:8][CH3:9])[C@@H:6]1[OH:16])(=[O:3])[CH3:2].[O-2].[Ba+2].[OH-].[Ba+2].[OH-].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([NH:4][C@H:5]1[C@@H:12]([O:13][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:11]([CH2:14][O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:10][C@@H:7]([O:8][CH3:9])[C@@H:6]1[O:16][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](NC(C)=O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: [Ba+2]
Agent: [O-2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](NC(C)=O)[C@H]1OCc1ccccc1

Procedure:
Dissolve 15 g. of methyl 3-acetamido-3-deoxy-β-D-galactopyranoside in DMF (300 ml.). To the solution add barium oxide (111 g.) and barium hydroxide (51 g.) and cool to 0°. With rapid stirring add benzyl bromide (150 ml.) dropwise. Allow the mixture to stir for a further 4 hours at 0° and then 16 hours at room temperature. Dilute the reaction mixture with 750 ml. of chloroform and filter. Concentrate the filtrate at 60° in vacuo to a yellow syrup, and extract this syrup with 500 ml of ethyl acetate. Filter the extract and concentrate in vacuo to a residue. Dissolve the residue in chloroform (200 ml.), wash the solution with 3 × 100 ml. of water then dry the chloroform phase over MgSO4. Remove the MgSO4 by filtration, then add hexane to the filtrate till crystals appear. After standing to complete the crystallization, filter off the product and dry to obtain methyl 3-acetamido-3-deoxy-2,4,6-tri-O-benzyl-β-D-galactopyranoside, 29.53 g. m.p. 147°-151°, [α d26 +52.5°.
Reaction SMILES: CN(C=O)C.I[C:7]1[C:12]([CH3:13])=[N:11][CH:10]=[CH:9][N:8]=1.[CH:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15].CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)(Cl)Cl>[CH3:13][C:12]1[C:7]([C:19]2[CH:20]=[CH:21][C:16]([CH:14]=[O:15])=[CH:17][CH:18]=2)=[N:8][CH:9]=[CH:10][N:11]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1nccnc1I
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nccnc1-c1ccc(C=O)cc1
Temperature: 90 °C

Procedure:
To a 100 ml round bottomed flask with stirring bar and an argon inlet was added Pd(OAc)2 (0.036 g, 0.15 mmol), bisdiphenylphosphinoferrocene (DPPF, 0.12 g, 0.2 mmol), and 15 ml of DMF were heated to 50° for 15 minutes. Cooled the reaction to room temperature then added 2-iodo-3-methyl-pyrazine (1.2 g, 5.4 mmol)(5). (a prep from Albert Hirschberg et al. J.Org. Chem. Jun.,1961 p1907-1912) and 4-formylbenzenboronic acid (0.90 g, 6.0 mmol) and Et3N (1.05 ml, 7.5 mmol). The mixture was heated to 90° C. for 10 h. Removed solvent in vacuo, taken up with CHCl3 and washed with diluted NH4OH. The organic layer was dried (MgSO4), filtered and concentrated to yield a black oil. This material was chromatographed (silica gel, 30% EtOAc/Hexane) to afford the title product.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C([O-])([O-])=O.[K+].[K+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCOCC1>[CH2:24]([O:23][C:21]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:22])[CH3:25]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
To 4.96 g (30 mmole) phenylalanine was added 76 mL of 1:1 mixture of water and dioxane, followed by 4.15 g (30 mmole) of K2CO3. After 10 min 2.87 mL of ethyl chloroformate (30 mmole) in 10 mL of dioxane was added dropwise, and the reaction mixture was allowed to stir. The reaction was monitored by TLC, and once complete (ca. 2 hrs) the solvent was stripped by rotary evaporation. The residue was reconstituted in 50 mL of 1N NaOH, then extracted with ethyl acetate. The aqueous layer was then acidified with 2N HCl to pH 2 and extracted 3× with ethyl acetate, after which the extract was dried over Na2SO4, filtered and the filtrate evaporated. The residue was pumped on high vacuum, after which it was recrystallized from Et2O/hexanes in two crops to give the title compound. NMR (300 MHZ, CD3OD): δ 7.22 (m, Ph, 5H), 4.38 (dd, Phe-α, 1H), 4.00 (q, CH3CH2OCOPhe, 2H), 3.17 (dd, Phe-β, 1H), 2.90 (dd, Phe-α, 1H), 1.17 (t, CH3CH2 OCOPhe, 3H).
Reaction SMILES: [CH2:1](N1C(C)(C)C(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O)[CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)[C:6]1=[O:26].I[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]I>>[CH2:4]([N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:50]2[CH:55]=[CH:54][C:53]([N+:19]([O-:21])=[O:20])=[C:52]([C:22]([F:23])([F:25])[F:24])[CH:51]=2)[C:6]1=[O:26])[CH2:3][CH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([F:24])([F:23])[F:25])[CH:14]=2)[C:6]1=[O:26]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Reactant: ICCCCCCI
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Yield: 27 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 1, 1,6-diiodohexane replacing 1,4-dibromobutane. The expected compound is obtained in the form of a light yellow solid with a yield of 27%. Melting point: 187-188° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[CH:21][CH:20]=1)[NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[Cl:16]>CO.[Ni]>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[CH:21][CH:20]=1)[NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[Cl:16]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.1 %

Procedure:
Ra—Ni (0.4 mL of 50% dispersion in water) was added to a solution of N-(2-chloro-4-nitrobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (1.04 g) in anhydrous MeOH (50 mL) and the mixture was stirred at room temperature under H2 atmosphere for 3.5 h. The mixture was then filtered over Celite and washed with MeOH. The filtrate was evaporated and the residue was purified by flash column chromatography (silica gel; eluent: CH2Cl2/MeOH 100:1 to 20:1) to give N-(4-amino-2-chlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (887 mg). ESMS: m/z 439 (MH+). The product obtained above was also prepared via the coupling of 4-(2-methoxyphenyl)-L-phenylalanine methyl ester hydrochloride with 4-amino-2-chlorobenzoic acid using EDC and HOBT in an analogous manner as described in Example 2.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 17.8 %

Procedure:
LAH (2.82 g, 0.15 mol, 1.5 eq) was dissolved in THF (50 ml), and to this solution was added dropwise a THF solution (50 ml) of 4-benzyloxyphenyl-acetonitrile (11.1 g, 0.05 mol, 1.0 eq) under ice-cooling. After the completion of the dropwise addition, the mixture was refluxed under heating for 1.5 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium sulfate solution (about 40 ml) was added under ice-cooling. After filtration through Celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroform/methanol=10/1) to give 2-(4-benzyloxyphenyl)ethylamine (2.02 g, 17.9%) as colorless needles.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[N+:19]([O-])=O.[H][H]>[Pt].C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[NH2:19]
Reactant: [H][H]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Oc2ccccc2)n1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(NCC(C)C)c(N)c(Oc2ccccc2)n1
Reaction time: 2 h

Procedure:
Toluene (150 ml), 5% platinum on carbon (1.55 g), and N-(2-methylpropyl)-6-methyl-3-nitro-2-phenoxypyridin-4-amine (31.00 g) from Part C were placed in a Parr hydrogenation flask at a hydrogen pressure of 345 kPa for 2 hours with shaking. The reaction was monitored by TLC and HPLC. More 5% platinum on carbon (5 g) was added. After 2 hours, another 4 g of 5% platinum on carbon was added and the reaction was continued overnight. The resulting reaction mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. After one hour the resulting brown oil solidified. NMR analysis of the solid (26.37 g) indicated sufficient purity for carrying the product on to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[O:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[OH-].[K+:26]>>[K+:26].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[O:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O-:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(C)C)OC(c1ccncc1)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)CC(OC(c1ccncc1)c1ccc(Br)cc1)C(=O)[O-]

Procedure:
Using the same protocol as described in example 17, step 5, methyl 2-[(4-bromophenyl)(pyridin-4-yl)methoxy]-4-methylpentanoate from step 2 (293 mg, 0.75 mmol) was hydrolysed with potassium hydroxide. The solid residue obtained was used as such in the next step.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH:24]([OH:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH:24]([OH:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: CCCCCCCCC(O)Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC(O)Cc1ccc(O)c(O)c1
Yield: 93.9 %

Procedure:
In 10 ml of ethanol was dissolved 0.5 g of 1-(3,4-dibenzyloxyphenyl)-2-decanol and the compound was catalytically reduced using 0.2 g of 10% palladium-carbon at room temperature and under atomospheric until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide 0.28 g of 1-(3,4-dihydroxyphenyl)-2-decanol. Oily product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:22])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.C(O)C.[OH-].[K+].Cl>O>[C:16]1([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7](=[O:22])[C:6]=2[C:4]([OH:5])=[O:3])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Yield: 93.1 %

Procedure:
A mixture of 1,2-dihydro-4-phenyl-2-oxo-3-quinoline carboxylic acid ethyl ester (5 g, 17 mmol), ethanol (20 ml), water (40 ml) and potassium hydroxide (5 g, mmol) was refluxed with heat for 1.5 hours. To the reaction mixture was added 60 ml of 2N-HCl to acidify the mixture to obtain a precipitated crystal by filtration. The crystal obtained was recrystallized from ethanol to give 4.2 g (yield: 92.9%) of the title compound.
Reaction SMILES: [Si](O[CH2:9][CH2:10][C:11]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)([CH3:13])[CH3:12])(C(C)(C)C)(C)C.CC1C=CC(S(OC[C@@H]2COC(C)(C)O2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:26][C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]2[CH:22]=[C:14]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][N:15]3[C:16]=2[CH:17]=1
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)CCn2c1cc1cc([N+](=O)[O-])c(F)cc12
Temperature: 90 °C
Yield: 48.3 %

Procedure:
To a solution of 2-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-yl)-6-fluoro-5-nitro-1H-indole (1.9 g, 5.0 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (2.86 g, 10.0 mmol) in DMF (10 mL) was added Cs2CO3 (4.88 g, 15.0 mmol). The mixture was heated at 90° C. for 24 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-50% ethyl acetate-hexane) to afford 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole (600 mg, 48%). ESI-MS m/z calc. 248.1, found 249.2 (M+1)+. Retention time 2.00 minutes; 2-(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-yl)-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indole (270 mg, containing some (R)-2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-yl)-6-fluoro-5-nitro-1H-indole). ESI-MS m/z calc. 494.2 and 380.2, found 495.4 and 381.4 (M+1)+. Retention time 2.12 and 1.92 minutes; (R)-3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-ol (1.0 g, containing some 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-ol). ESI-MS m/z calc. 380.2 and 266.1, found 381.2 and 267.2 (M+1)+. Retention time 1.74 and 1.48 minutes.
Reaction SMILES: [OH-].[K+].[CH3:3][Si:4]([CH3:17])([CH3:16])[C:5]1[O:9][CH:8]=[C:7]([CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[CH:6]=1>C(O)C.O>[CH3:17][Si:4]([CH3:3])([CH3:16])[C:5]1[O:9][CH:8]=[C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=1
Reactant: COC(=O)CCc1coc([Si](C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)c1cc(CCC(=O)O)co1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of potassium hydroxide (446 mg, 7.96 mmol) in 95% ethanol/water (4 ml) was added to a solution of methyl 3-(5-trimethylsilyl-3-furyl)propionate(1.2 g, 5.3 mmol), prepared as in Example 2, in 95% ethanol/water (4ml) at 0°. After stirring at 0° for 5 hours and at room temperature for 5 hours, most of the solvent was evaporated. The residue was dissolved in ethyl acetate (15 ml), acidified with hydrochloric acid and the mixture then extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which on crystallization from hexane (-78°) gave the title acid as colorless needles, mp ca. 25°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:8][C:6]1[CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: C1COCCN1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Brc1cncc(N2CCOCC2)c1
Yield: 64.8 %

Procedure:
To a solution of 3,5-dibromopyridine (XL) (1.68 g, 7.1 mmol) in dioxane (14 mL) was added morpholine (682 mg, 7.8 mmol), CsCO3 (3.24 g, 9.93 mmol) and xantphos (123 mg, 0.21 mmol). The solution was degassed before adding Pd2(dba)3 (195 mg, 0.21 mmol). The reaction was microwaved at 90° C. for 4 h. The reaction was poured into a mixture of CHC13/H20; the aqueous layer was separated, washed with water, then brine and concentrated under vacuum. The crude product was purified on a silica gel column (100% hexane→1:3 EtOAc:hexane) to give 4-(5-bromopyridin-3-yl)morpholine (XLI) as a yellow solid (1.12 g, 4.6 mmol, 65% yield). ESIMS found C9H11BrN2O m/z 244 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:40])[N:5]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3COCC[Si](C)(C)C)[CH3:13])=[N:7]2.OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CO>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:40])[N:5]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][NH:19]3)[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#N)c3)c(=O)c12
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Solvent: CO
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(C#N)c3)c(=O)c12

Procedure:
Compound 141 was treated with 4N HCL in MeOH for 1 hour using the procedure described for compound 121 (step B) to provide compound 140. m/z=423 (M+H). The structure of compound 140 is shown below.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:22])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][CH:30]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH:34][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:22])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:31][CH:30]=1)[CH3:24]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(OCc2cccs2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCc3cccs3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-(thiophen-2-ylmethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: Cl.[N:2]1[C:3]([NH2:11])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12>C(O)C.[Pd]>[N:2]1[C:3]([NH2:11])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: Nc1nc2ccccn2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1nc2n(n1)CCCC2
Reaction time: 72 h

Procedure:
The 12.7% solution of HCl in ethanol (5.35 mL) and 10% Pd—C (50% wet) (2.5 g) were added to the mixture of [1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.5 g) in ethanol (72 mL). The reaction mixture was hydrogenated at 400 KPa of H2 for 3 days at room temperature. The mixture was filtered and concentrated under reduced pressure. The residue was treated with saturated potassium carbonate solution and extracted with chloroform. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a pale yellow solid (2.31 g, 90%). 1H-NMR (400 MHz, CDCl3) δ 1.88–1.94 (m, 2H), 1.98–2.05 (m, 2H), 2.77 (t, 2H, J=6.2 Hz), 3.95 (t, 2H, J=6.2 Hz), 4.09 (brs, 2H).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]1.CCN(CC)CC.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C(Cl)Cl>[C:24]([N:7]1[CH2:6][C:5]2([CH2:1][CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]2)[CH2:9][CH2:8]1)(=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCC2(CCN(C(=O)OC(C)(C)C)C2)C1
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl 3,7-diazaspiro[4.4]nonane-3-carboxylate (127 mg, 0.56 mmol) in anhydrous DCM (1 mL), cooled in an ice water bath was added Et3N (57 mg, 78 μL, 0.56 mmol), followed by the addition of propanoyl chloride (57 mg, 54 μL, 0.62 mmol) as a solution in DCM (0.2 mL). The reaction mixture was stirred for 20 minutes, diluted with DCM and was washed with 1M HCl (×2) and brine (×1). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl 3-propanoyl-3,7-diazaspiro[4.4]nonane-7-carboxylate (154 mg, 97%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 3.73-3.11 (m, 8H), 2.34-2.17 (m, 2H), 1.97-1.70 (m, 4H), 1.46 (s, 9H), 1.16 (t, J=7.4 Hz, 3H). LC/MS m/z 283.5 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCC>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)=[CH:31][CH:30]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1cccc(OC2CCNc3ncc(-c4ccc(N5CCOCC5)cc4)cc32)c1
Yield: 73 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 4-morpholinophenylboronic acid (20.7 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (73% yield). M.p. 124-126° C., LCMS: m/z=422.28 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, 1H), 2.22-2.5 (m, 1H), 3.17 (t, J=4.7 Hz, 4H), 3.38-3.48 (m, 1H), 3.54-3.67 (m, 1H), 3.87 (t, J=4.7 Hz, 4H), 5.10 (s, 1H), 5.37 (t, J=1.0 Hz, 1H), 6.88-7.02 (m, 4H), 7.03-7.07 (m, 1H), 7.21-7.26 (m, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.56 (d, J=1.9 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[N:11]=[C:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:13][C:14](=[O:24])[C:15]=1[N:16]=NC1C=CC=CC=1>O.CN(C)C=O>[NH2:9][C:10]1[N:11]=[C:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:13][C:14](=[O:24])[C:15]=1[NH2:16]
Reactant: Nc1nc(Cc2ccccc2)[nH]c(=O)c1N=Nc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cc2ccccc2)[nH]c(=O)c1N
Yield: 64.8 %

Procedure:
A solution of sodium dithionite (62 g.) in water (300 ml.) was added dropwise during 30 minutes to a solution of 4-amino-2-benzyl-5-phenylazopyrimid-6-one (27 g.) in dimethylformamide (1000 ml.) at 75° C. The mixture was cooled, and the insoluble solid was filtered off. The filtrate was evaporated in vacuo, the residue was stirred with water, and the solid filtered off. This solid was extracted with boiling water (250 ml.), the extract was filtered hot and then cooled. The solid which separated was recrystallised from water to give 4,5-diamino-2-benzylpyrimid-6-one (12.4 g.) in the form of off-white needles, m.p. 243° C. (with decomposition).