Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.[CH2:11]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:20])[CH2:12][C:13]#[CH:14].C(#N)C.C(NC(C)C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I>[CH3:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH2:11][CH2:12][C:13]1[O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH:14]=1
Reactant: C#CCCN1CCC[C@H]1C
Reactant: N#Cc1ccc(O)c(I)c1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
The product from Example 87A (10.0 g, 40.81 mmol) was sequentially treated with 0.1M (2R)-1-(3-butynyl)-2-methylpyrrolidine in acetonitrile (490 mL, 48.9 mmol), Pd(OAc)2 (0.275 g, 1.22 mmol), Ptol3 (0.747 g, 2.44 mmol), and copper iodide (1.16 g, 6.122 mmol). After stirring at 25° C. for 10 min, diisopropyl amine (43.0 mL) was added and the reaction mixture was heated at 60° C. in an inert atmosphere for 16 h. The reaction mixture was cooled, filtered through celite, concentrated under reduced pressure, and purified on silica gel using 95% DCM, 9.5% MeOH, 0.1% NH4OH to provide the title compound as a brown semi-solid (2.56 g, 24.6% yield). 1HNMR (300 MHz, CD3OD) δ 1.09 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 1.81 (m, 2H), 2.02-2.38 (m, 2H), 2.59 (m, 2H) 3.08 (m, 2H), 3.28 (m, 2H), 6.70 (s, 1H), 7.58 (s, 1H), 7.97 (s, 1H); MS (ESI) m/e 255 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-methoxycarbonyl-phenoxymethyl)-piperidine-1-carboxylic acid t-butyl ester (8.5 g, 24.61 mmol) in DCM (150 mL) was added TFA (45 mL) and the mixture was stirred for 2 hrs at room temperature. The volatiles were evaporated in vacuo and the residue crystallised from addition of diethyl ether. The solid was filtered off washed with a small portion of diethyl ether and dried. This afforded 8.8 g (99%) of 4-(piperidin-4-ylmeth-oxy)-benzoic acid methyl ester as a TFA salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:21])=[O:38])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(SC)cc2)n1-c1ccc(C#N)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2ccc(S(C)=O)cc2)n1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of ethyl 3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoate (23A) (98 mg, 0.23 mmol) in DCM (1 mL) was added m-CPBA below 0° C. by five portions. Then the reaction mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete. The mixture was diluted with DCM (10 mL) and washed with sat. NaHCO3 (15 mL), dried over Na2SO4, filtered and concentrated to afford a yellow oil, which was purified by silica gel column chromatography to afford ethyl 3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoate (23B) as a light yellow solid (65 mg, 65%).
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=1)=[O:27].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]([NH:28][C:29]4[CH:30]=[C:31]([O:39][CH3:40])[C:32]([O:37][CH3:38])=[C:33]([O:35][CH3:36])[CH:34]=4)=[O:27])[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Reactant: COc1cc(NC(=O)CBr)cc(OC)c1OC
Agent: I
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CN2CCCC(n3c(=O)c4c(C)onc4c4c(Cl)cccc43)C2)cc(OC)c1OC
Yield: 63.2 %

Procedure:
Add 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol), 2-bromo-N-(3,4,5-trimethoxy-phenyl)-acetamide (38 mg, 0.12 mmol), and tetrahydrofuran (3 mL) to a roundbottom flask. Stir and add potassium iodide (2 mg, 0.01 mmol) and potassium carbonate (34 mg, 0.25 mmol) at room temperature under nitrogen overnight. Concentrate the reaction, partitions between water and 20% isopropanol/chloroform, and separate. Was the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–0.5% methanol/chloroform) to give 37.6 mg of the title compound as an orange solid, 62% yield. 1H NMR: consistent with structure. MS (ion spray) 541 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]([C:21]([OH:23])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]([C:21]([OH:23])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1N)C(=O)O
Yield: 84.4 %

Procedure:
In 500 ml of methanol is dissolved 30 g of O-(o-nitrophenyl)-Boc-L-serine obtained in Example 1, and catalytic reduction is conducted in a stream of hydrogen at ordinary temperature and at atmospheric pressure with 1 g of 10% palladium-carbon used as a catalyst. The catalyst is filtered off, and the filtrate is concentrated under reduced pressure. The resulting residue is recrystallized from ethyl acetate to give 23 g of O-(o-aminophenyl)-Boc-L-serine as colorless crystals, melting at 90°-91° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[CH:1][CH:3]([CH3:8])[CH3:4])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 188.5 %

Procedure:
To a 300 mL volume three-necked flask, 20.0 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 76 ml of methanol and 12.3 g of isobutylaldehyde were added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and then hexane was added thereto. The precipitated crystals were collected by filtration and dried under reduced pressure to give 23.2 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(2-methyl-1-propylidene)hydrazine ((40-a)-(14)-4).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]1[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[CH3:7][N:8]1[C:12]([NH:13][C:15](=[O:17])[CH3:16])=[CH:11][C:10]([CH3:14])=[N:9]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Pyridine (7.1 mL, 90 mmol) was added to a solution of 2,5-dimethyl-2H-pyrazol-3-ylamine (10 g, 90 mmol) in acetic anhydride (46 mL) at 0° C. and the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under vacuum to yield the title compound as a brownish liquid (13.7 g), yield: 100%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[C:16]=1Cl)([O-:14])=[O:13].Cl>CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:16]2[C:17]([C:24]([F:26])([F:27])[F:25])=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1ncc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ncc(Cl)cc2Cl)c(C(F)(F)F)c1

Procedure:
In 20 ml. of dimethylformamide, 1.65 g. of 2-amino-3,5-dichloropyridine was dissolved and 1.0 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, 2.7 g. of 2,4-dinitro-6-trifluoromethylchlorobenzene was added at 30° C. during 5 minutes to react them for about 3 hours. The reaction mixture was acidified with conc. HCl and the product was extracted with methylenechloride. The extracted layer was washed with water and dehydrated and the solvent was distilled. The product was separated by a silica gel column with an eluent of toluene and the solvent was distilled off to obtain 2.5 g. of the object compound having the melting point of 98° to 101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([CH3:22])=[CH:20][N:19]=[CH:18][C:17]=1[Br:23])[OH:15]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:21]([CH3:22])=[CH:20][N:19]=[CH:18][C:17]=1[Br:23])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(C)cncc2Br)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(C)cncc2Br)c(OC)c1OC
Yield: 55 %

Procedure:
3 g of manganese dioxide was added to a toluene (30 ml) solution of 0.43 g (1.1 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(3-bromo-5-methyl-4-pyridyl)methanol obtained in step (b), followed by stirring under reflux by heating for 2 hours. The mixture was subjected to filtration, the solvent was distilled off under reduced pressure, and the crude product thus obtained was purified by silica gel column chromatography to obtain 0.23 g (yield 54%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-bromo-5-methylpyridine (compound No. 228; m.p. 88-93° C.).
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28]C(=O)OC(C)(C)C)=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36]>C(OCC)(=O)C.CO>[ClH:36].[ClH:36].[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH2:28])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 90 %

Procedure:
A mixture of tert-butyl (1R,25)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexylcarbamate (2.71 g, 5.7 mmol), a 4N hydrogen chloride in ethyl acetate solution (10 ml) and methanol (30 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound (2.29 g, 90%) as a colorless powder.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([CH:30]=1)[C:9]([NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([S:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=S)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:10].S([O-])([O-])=[O:34].[Na+].[Na+].Cl>[OH-].[Na+]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([CH:30]=1)[C:9]([NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([S:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:34])(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:10]
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=S)NC(C)C)CC1
Agent: Cl
Agent: OO
Agent: [Na+]
Product: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=O)NC(C)C)CC1
Reaction time: 2 h
Yield: 45.6 %

Procedure:
0.1 ml (1.16 mmol) of 30% strength hydrogen peroxide solution was added to a solution of 48 mg (0.1 mmol) of 5-chloro-2-methoxy-N-(2-(1-(3-isopropylthioureidosulfonyl)piperidin-4-yl)ethyl)benzamide in 2 ml of 0.5 M sodium hydroxide solution at 0° C. After the reaction mixture had been kept at 0° C. for 2 hours, 100 mg of sodium sulfite were added, and the mixture was acidified by means of 2 M hydrochloric acid. The precipitated solid was filtered off, washed with water until neutral and recrystallized from diethyl ether. 21 mg (45%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26].C([O-])([O-])=O.[K+].[K+].CC(=O)CC>O>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH2:16]
Reactant: C=CCCCCCCCCCBr
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Yield: 41 %

Procedure:
A mixture of 10 g (0.053 mol) of 4,4′-Dihydroxy-biphenyl, 12.52 g (0.053 mol) of 11-Bromo-1-undecene, 7.42 g (0.053 mol) of K2CO3 and 120 mL of dry butanone is refluxed for 24 h, then the reaction mixture is allowed to return to room temperature. 100 mL of water is added, then the product is filtered off, washed with water and methanol. The resulting solid is recrystallised three times from butanone to give a pure white product (7.35 g, 41% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19](Cl)[N:18]=3)([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:35]2[C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=[C:34]2[CH2:32][CH3:33])[N:18]=3)([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.0 g, 6.62 mmol), 2-ethylbenzimidazole (1.16 g, 7.94 mmol), tris(dibenzylideneacetone)dipalladium (152 mg, 0.17 mmol), XPhos (316 mg, 0.66 mmol) and K3PO4 (2.81 g, 13.24 mmol) in dioxane (80 mL) was purged with N2 then heated at 90° C. for 22 h before further tris(dibenzylideneacetone)dipalladium (152 mg, 0.17 mmol) and XPhos (316 mg, 0.66 mmol) were added. The resulting mixture was heated at 100° C. for 65 h then diluted with 2-methyl THF and filtered through a silica plug. The filtrate was washed with H2O and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:cyclohexane, 20-85%) affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.15 g, 85%). LCMS (method H): RT 2.87 min, [M+H]+ 563.5
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[O:26][N:25]=2)=[CH:20][CH:19]=1>CC#N>[N:1]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[O:26][N:25]=3)=[CH:22][CH:23]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(Cn3cnc4ccccc43)cc2)no1
Temperature: 60 °C
Yield: 47.5 %

Procedure:
A mixture of benzimidazole (24 mg, 0.20 mmol), K2CO3 (0.2 mmol), and 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 25 mg, 0.09 mmol) in CH3CN (1 mL) was heated overnight at 60° C. The mixture was filtered and the solvent was evaporated from the filtrate. The residue was purified by chromatography to give 3-(4-benzoimidazol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (13.6 mg, 48%). Based on the NMR, the purity was estimated as 80%.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:50][O:51][CH:52]1[CH2:57][CH2:56][CH2:55][N:54]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([CH2:65][NH:66][CH3:67])=[CH:61][CH:60]=2)[CH2:53]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:66]([CH2:65][C:62]3[CH:61]=[CH:60][C:59]([CH2:58][N:54]4[CH2:55][CH2:56][CH2:57][CH:52]([O:51][CH3:50])[CH2:53]4)=[CH:64][CH:63]=3)[CH3:67])=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (28 mg, 0.16 mmol), HOBt (21 mg, 0.16 mmol) DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (36 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [OH-].[Na+].[N:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13][C:14]([O:16]CC)=[O:15])[CH:4]=1.Cl>O1CCOCC1>[N:3]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:4]=1
Reactant: CCOC(=O)Cc1cnc2cccnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1cnc2cccnc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (10 mL, 2.0 M) was added to ethyl 1,5-naphthyridin-3-ylacetate in 1,4-dioxane (10 mL) and the mixture was heated at 100° C. for 6 hours. The reaction mixture was cooled to room temperature and acidified to pH 4 using aqueous 2M HCl and then evaporated in vacuo. The residue was azeotroped with toluene (2×15 mL) then dissolved in THF (50 mL) and stirred at 40° C. for 30 min. The mixture was filtered, the filtrate was evaporated in vacuo and the residue was triturated with diethyl ether to afford the title compound as an off white solid, 200 mg.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32]C(OC)=O)=[CH:27][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1.O.[ClH:38]>CO>[ClH:38].[F:3][C:4]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:5]=1[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCn4ccnc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCn1ccnc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
2M Aqueous sodium hydroxide (0.3ml , 6 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (257 mg, 5.5 mmol) in methanol (5 ml) and the mixture stirred for 1 hour at 40° C. Water and 1M hydrochloric acid (0.6 ml) were added and the mixture concentrated to half volume by evaporation. The resulting solid was collected by filtration, dissolved in methylene chloride/methanol and a solution of 7M hydrogen chloride in isopropanol (0.4 ml) was added. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (160 mg, 60%).
Reaction SMILES: [N:1]([C@@H:4]([C@H:6]1[CH2:10][O:9][C:8](=[O:11])[N:7]1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@H:19]([C:21]2[S:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:23][CH:22]=2)[CH3:20])[N:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[NH2:1][C@@H:4]([C@H:6]1[CH2:10][O:9][C:8](=[O:11])[N:7]1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@H:19]([C:21]2[S:25][C:24]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[N:23][CH:22]=2)[CH3:20])[N:13]=1)[CH3:5]
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)N=[N+]=[N-])n1)c1cnc(-c2ccc(Cl)cc2)s1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)N)n1)c1cnc(-c2ccc(Cl)cc2)s1
Yield: 15.3 %

Procedure:
To a round bottom flask containing (S)-4-((R)-1-azidoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (14 mg, 0.03 mmol) and stir bar was added THF (1 mL) and trimethylphosphine (0.06 mL, 0.06 mmol, 1.0 M in THF). The resulting reaction mixture allowed to stir 2 hr at RT. A second addition of trimethylphosphine (0.06 mL, 0.06 mmol) occurred and the mixture allowed to stir 1.5 hr at RT. Reaction was quenched by the addition of a saturated solution of NH4Cl and EtOAc. The phases were partitioned and aqueous phase extracted with EtOAc. Organic phases combined and washed with brine, dried (Na2SO4), filtered and concentrated to a yellow residue. Residue dissolved in DMSO and purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford (S)-4-((R)-1-aminoethyl)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (2.6 mg, 4.60 μmol, 15% yield) as a TFA salt.