Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:21])[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+].C([O-])(=O)C(C1C=CC=CC=1)O>CC(C)=O>[C:1]1([CH2:7][O:8][C:9](=[O:21])[CH:10]([OH:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:23][CH2:24][CH2:25][Cl:26])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: COc1cc(C(O)C(=O)OCc2ccccc2)ccc1O
Agent: O=C([O-])C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(O)C(=O)OCc2ccccc2)ccc1OCCCCl
Yield: 21.8 %

Procedure:
A mixture of 2.92 g (0.008 mole) of 4-hydroxy-3-methoxymandelic acid (phenylmethyl) ester, 2 ml (0.02 mole) of 1-bromo-3-chloropropane, and 2.80 g (0.02 mole) of potassium carbonate in 40 ml of acetone was heated at reflux for 16 hours under nitrogen atmosphere during which time the solution changed from colorless to light-yellow. TLC (silica gel, hexanes/acetone 4:1) showed that the mandelate derivative had reacted, but 30-40% of unknown impurities had formed. The inorganic materials were separated by filtration, washed with acetone, and the filtrate was concentrated in vacuo at 60° C. to give 3.65 g of crude product. The material was purified by column chromatography (diameter 25 mm, using 80 g of silica gel) eluted with cyclohexane/ethyl acetate (6:1). The fractions containing the product were collected and the solid recrystallized from ethyl ether/hexanes to give 0.637 g (22%) of material as a white powder.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:49])C=1>ClCCCl.C(=O)([O-])O.[Na+]>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][S:15]([CH3:16])=[O:49])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:23][C@H:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCSC)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCS(C)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (150 mg) was dissolved in 1,2-dichloroethane (3 ml), 3-chloroperbenzoic acid (65% contained, 70 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (10:90-85:15) and concentrated under reduced pressure to give the object compound (113 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][O:10][C:9]2=[O:19])[C:5]([F:20])=[CH:4][N:3]=1.[CH:21]1([C@@H:24]([NH2:26])[CH3:25])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:21]1([C@@H:24]([NH:26][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][O:10][C:9]3=[O:19])[C:5]([F:20])=[CH:4][N:3]=2)[CH3:25])[CH2:23][CH2:22]1
Reactant: O=C1OC[C@H](c2ccccc2)N1c1nc(Cl)ncc1F
Reactant: C[C@H](N)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2c2ccccc2)n1)C1CC1
Temperature: 127.5 °C
Yield: 55.8 %

Procedure:
A mixture of (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-phenyloxazolidin-2-one (40 mg, 0.136 mmol), (S)-1-cyclopropylethanamine (34.8 mg, 0.409 mmol), Hunig's Base (0.119 mL, 0.681 mmol) in DMSO (0.4 mL) was heated under argon at 105-115° C. for ˜18 hrs (alternative: 120-135° C. for ˜90 min). Then mixture was allowed to cool to room temperature. The mixture was diluted with DMSO and water (˜10 vol. % of DMSO), filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (S)-3-(2-((S)-1-cyclopropylethylamino)-5-fluoropyrimidin-4-yl)-4-phenyloxazolidin-2-one (26 mg) as a white solid as its trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]1[C:5]([Cl:6])=[N:4][O:3][C@@H:2]1[C@H:7]([NH2:11])[C:8]([OH:10])=[O:9].[C:12]1([CH2:25][O:26][C:27](Cl)=[O:28])[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[K+].Cl>O>[Cl:6][C:5]1[CH2:1][CH:2]([CH:7]([NH:11][C:27]([O:26][CH2:25][CH:12]2[C:24]3[CH:16]=[CH:17][CH:18]=[CH:19][C:23]=3[C:22]3[C:13]2=[CH:14][CH:15]=[CH:20][CH:21]=3)=[O:28])[C:8]([OH:10])=[O:9])[O:3][N:4]=1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Reactant: N[C@H](C(=O)O)[C@@H]1CC(Cl)=NO1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: O=C(NC(C(=O)O)C1CC(Cl)=NO1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of AT-125 (178 mg; 1 mmole), 9 fluorenylmethylchloroformate (285 mg, 1.1 mmole), and potassium bicarbonate (370 mg; 3.7 mmole) in 5 ml of water was stirred for 20 hours at room temperature. The gelatinous mixture is acidified to pH 2 with hydrochloric acid, evaporated to dryness under reduced pressure, and extracted with acetone. The acetone extracts are adsorbed onto silica gel and chromatographed on 40 g of silica gel with methylene chloride:isopropanol:acetic acid (100:3:1). Fractions of 20 ml are collected and monitored by TLC (U.S. visualization). The first 8 fractions contain components derived from the chloroformate reagent only including 9 fluorenylmethyl alcohol. Fractions 11-17 contain 206 mg of chromatographically homogeneous 3-chloro-α-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4,5-dihydro-5-isoxazoleacetic acid, and fractions 21-50 contain 132 mg of chromatographically homogeneous 3-chloro-α-[[(3-chloro-4,5-dihydro-5-isoxazolyl)- [[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetyl]amino]-4,5-dihydro-5-isoxazoleacetic acid. Crystallization of fractions 11-17 from aqueous methanol and recrystallization from acetone-cyclohexane yields 3-chloro-α -[[(9H-fluoren-9ylmethoxy)carbonyl]amino]-4,5-dihydro-5-isoxazoleacetic acid m.p. 175°-176°.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH2:18].C(N(CC)CC)C>C(#N)C.O>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: CCCS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Propane-1-sulfonyl chloride (5.63 mL, 50 mmol) was added to a solution of 2-methyl-5-nitro-phenylamine (7.61 g, 50 mmol) and triethylamine (7 mL) in acetonitrile (100 mL). The resulting solution was vigorously stirred for 3 h at room temperature and diluted with cold water (500 mL), which lead to the formation of a precipitate. The precipitate was filtered out, washed with 1N HCl (100 mL), water (2×200 mL) and dried to give 10.2 g (79%) of propane-1-sulfonic acid (2-methyl-5-nitro-phenyl)-amide as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:24][CH2:23][CH2:22][C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]1=2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[N:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ncccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cccnc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methyl-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:13][CH2:14][C@@H:15]1[CH2:20][NH:19][C@@H:18]([CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:17][N:16]1[C:27]([O:29][CH3:30])=[O:28].[OH-].[Li+]>ClCCl.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:19]2[C@@H:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:17][N:16]([C:27]([O:29][CH3:30])=[O:28])[C@H:15]([CH2:14][OH:13])[CH2:20]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)N1C[C@H](CN2CCCC2)NC[C@H]1CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)N1C[C@H](CN2CCCC2)N(C(=O)Cc2ccc(Cl)c(Cl)c2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of 1,1'-carbonyldiimiazole (0.20 g, 1.26 mmol) in dichloromethane (10 mL) was added portionwise 3,4-dichlorophenylacetic acid (0.25 g, 1.26 mmol) and the resulting solution stirred under nitrogen for 1 hr, at room temperature. A solution of 8 (0.13 g, 0.5 mmol) in dichloromethane (10 mL) was added and the mixture was allowed to stand at room temperature for 18 hr. The reaction mixture was washed with sodium carbonate solution (2 N, 2×10 mL), dried, and evaporated to give a viscous oil. This material was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL) and treated with lithium hydroxide (42 mg, 1.0 mmol). The reaction mixture was removed, and the aqueous residue was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried and evaporated to give a colorless gum which was purified by flash column chromatography on silica gel, eluting with ethyl acetate-methanol (40:1) to give 9 (155 mg, 70%) as a colorless foam.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C@@H:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[C:17]([OH:19])=O)[CH:10]=2)[NH:5][CH:4]=1)#[N:2].Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]=[C:3]2[C:1]#[N:2])=[O:19]
Reactant: N#Cc1c[nH]c2ccc([C@@H]3CCC[C@H]3C(=O)O)cc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H]1CCC[C@H]1c1ccc2[nH]cc(C#N)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of trans-2-(3-Cyano-1H-indol-5-yl)-cyclopentanecarboxylic acid (0.66 g, 2.60 mMol), N,O-dimethylhydroxylamine hydrochloride (0.51 g, 5.20 mMol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g, 2.86 mMol), and dichloromethane (20 mL) was treated with triethylamine (1.05 g, 10.4 mMol) and stirred at ambient temperature for 18 h. The resulting solution was diluted with 30 mL dichloromethane, washed with 1M hydrochloric acid, 1M sodium hydroxide, and brine, dried over sodium sulfate and concentrated in vacuo to give the crude product as a clear oil which was used without further purification (0.51 g, 66%). LC-MS: 1.38 min (2 min gradient); 298.11 (MH)+.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([N:21]1[CH:25]=[C:24]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[CH:23]=[N:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH:25]=[C:24]([CH2:26][N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[CH:23]=[N:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CC(C)c1ccc(NCc2cnn(Cc3ccccc3)c2)cc1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3)c2)C(=O)C2CCCc3ccccc32)cc1
Yield: 80.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.26 g) and [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.46 g) as starting materials, N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) was obtained.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([NH2:13])=[S:12])([CH2:4]3)[CH2:2]2.Br[C:15]1([C:21](OC)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]1[S:12][C:15]4([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:21](=[O:22])[N:13]=1)([CH2:4]3)[CH2:2]2
Reactant: NC(=S)NC12CC3CC(CC1C3)C2
Reactant: COC(=O)C1(Br)CCCCC1
Product: O=C1N=C(NC23CC4CC(CC2C4)C3)SC12CCCCC2

Procedure:
Synthesis was performed from N-tricyclo[3.3.1.0˜3,7˜]non-3-ylthiourea and methyl 1-bromocyclohexanecarboxylate according to Method D.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:40]=[CH:39][CH:38]=[C:37]4[C:32]=3[CH:33]=[CH:34][CH:35]=[N:36]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Nc1cccc2ncccc12
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc4ncccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 86.4 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.10 g, 0.24 mmol) obtained in Example 19, step 4 and 5-aminoquinoline (0.069 g, 0.48 mmol), the title compound (0.108 g, 86%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([NH:15][C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=C(O)CCc1cccc([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)CCc2cccc([N+](=O)[O-])c2)c1
Reaction time: 16 h

Procedure:
A solution of 3-(3-nitrophenyl)propanoic acid (0.43 g, 2.2 mmol) and tert-butyl (3-aminophenyl)carbamate (0.50 g, 2.4 mmol) in acetonitrile (16 mL) was treated with O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 g, 3.3 mmol) followed by N,N-diisopropylethylamine (0.57 mL, 3.3 mmol) and stirred for 16 h. The reaction mixture was concentrated and diluted with brine (80 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude residue. This material was purified by flash column chromatography to give the desired product (0.87 g, 98%) as an off-white foam. LCMS for C16H16N3O5 ([M-(t-Bu)+H]+H)+: m/z=330.0.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:22][C:23]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:23]=3[OH:22])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCc1ccc(O)cc1O
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Product: COc1ccc(C(=O)NCc2ccc(O)cc2O)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.03 g of the target compound is obtained as white solid in substantially the same manner as in Example 11, except for using 3-adamantan-1-yl-4-methoxybenzoic acid instead of 3-adamantan-1-yl-4-hydroxybenzoic acid and using 2,4-dihydroxybenzylamine instead of 3,4-dihydroxybenzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:12]/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:16][C:15](=[O:17])/[CH:14]=[CH:13]/[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: COc1ccc(C(=C/C=C/C(=O)O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 0.5 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
As in Example 115, (E)-5,5-bis (3,4-dimethoxyphenyl)-2,4-pentadienoic acid (16 g) and 4-nitrophenol (6.6 g) in dichloromethane (160 mL) was treated with 1,3-dicyclohexylcarbodiimide (9.3 g). The mixture was stirred at 0.5° C. for 1 hour, then at room temperature for 18 hours. After the usual work up, the crude product was triturated with ether to give 13.2 g of (E)-5,5-bis (3,4-dimethoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester. Crystallization of a portion from ether afforded the analytical sample, mp 140°-142° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:18][N:19](C)C=O>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:18]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of tert-butyl [(1S)-1-(4-bromophenyl)ethyl]carbamate (step 1 of Example 5, 1.50 g, 5.00 mmol), tetrakis(triphenylphosphine)palladium (0) (0.58 g, 0.50 mmol), zinc cyanide (0.59 g, 5.00 mmol) and N,N-dimethylforamide (30 mL) was stirred at 80° C. for 16 h under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with ether (200 mL) and washed with water (100 mL×3). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4:1) to afford 1.11 g (90%) of the title compounds as colorless syrup: 1H-NMR (CDCl3) δ 7.64–7.61 (2H, m), 7.41 (2H, d, J=8.3 Hz), 4.83 (2H, br.s), 1.44–1.42 (12H, m).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)#[C:2][CH3:3].[NH2-].[Li+].[CH3:13][CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18]Br>CS(C)=O>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH2:1][C:2]#[C:3][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH3:20])[CH3:13]
Reactant: CC(C)CCCCBr
Reactant: CC#COC1CCCCO1
Agent: [Li+]
Agent: [NH2-]
Solvent: CS(C)=O
Product: CC(C)CCCCC#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(0.5 mole) of prop-1-ynyltetrahydropyranyl ether in 200 ml of dimethyl sulfoxide were added with stirring to a solution of 11.5g. (0.5 mole) of lithium amide in 200 ml of dimethyl sulfoxide. Stirring was continued for 1 hour and 5-methylhexyl bromide 89g. (0.5 mole) were added over 45 min. External cooling was necessary to keep the temperature at 30° C. After 3 hours, the mixture was poured into 1 liter of ice-water. The mixture was extracted with petrol-ether, and the organic phase washed with 10% sulfuric acid, and then water. The solution was dryed over magnesium sulfate concentrated and distilled at 100°-103° C/0.01mm to give 82.6 (70%) of 8-methylnon-2-ynyl tetrahydropyranyl ether.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:24]([C:23]3[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:22]=3[F:21])=[O:25])[CH2:2][CH2:3]2)[N:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccc(F)cc4F)CC3)cccc2n1
Yield: 71 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 2,4-difluorobenzoyl chloride (65 mg; 0.37 mmol) via Method AA to yield 108 mg. (71% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.48 (m, 1H), 7.35 (m, 2H), 7.18 (m, 3H), 6.77 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.53 (br d, J=13.2 Hz, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.44 (m, 1H), 3.12 (t, J=12.8 Hz, 1H), 2.85 (m, 1H), 2.22 (m, 1H), 1.9 (d, J=12.4 Hz, 1H), 1.74 (d, J=12.4 Hz, 1H), 1.26 (m, 2H). MS m/z (ESI) 414 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)[CH:5]=[CH:6][CH:7]=1.C[O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1>>[CH2:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C:29]([OH:39])=[O:28])=[CH:36][CH:35]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: Cc1cccc2c(-c3cccc(N)c3)c(C(=O)c3ccccc3)cnc12
Product: Cc1cccc2c(-c3cccc(NCc4ccc(CC(=O)O)cc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-methyl-quinolin-3-yl]-phenyl-methanone and (4-formyl-phenyl)-acetic acid methyl ester according to the procedure of Example 66. MS (ES) m/z 473.3.