Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([F:25])=[C:11]([C:16]3[C:17]([C:23]#[N:24])=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:12]([F:15])=[CH:13][CH:14]=2)O1.Br[C:28]1[N:32]2[N:33]=[CH:34][C:35]([C:37]([F:40])([CH3:39])[CH3:38])=[N:36][C:31]2=[N:30][CH:29]=1>>[F:40][C:37]([C:35]1[CH:34]=[N:33][N:32]2[C:28]([C:9]3[C:10]([F:25])=[C:11]([C:16]4[C:17]([C:23]#[N:24])=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)[C:12]([F:15])=[CH:13][CH:14]=3)=[CH:29][N:30]=[C:31]2[N:36]=1)([CH3:39])[CH3:38]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2F)OC1(C)C
Reactant: CC(C)(F)c1cnn2c(Br)cnc2n1
Product: CC(C)(F)c1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3F)cnc2n1
Yield: 38 %

Procedure:
3′-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,2′,6′-trifluorobiphenyl-2-carbonitrile was reacted with 7-bromo-3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine by a similar procedure to that described in Example 2, step e, to give the title compound in 38% yield as a yellow solid: mp 166-169° C. (EtOAc-isohexane); 1H NMR (360 MHz, CDCl3) δ 1.85 (6H, d, J 22.1); 7.25 (1H, td, J 8.6, 1.4), 7.46 (1H, td, J 8.6, 2.7), 7.54–7.59 (2H, m), 8.30 (1H, dt, J 8.3, 6.2), 8.35 (1H, d, J 3.0), 8.80 (1H, d, J 1.2); MS (ES+) m/z 412 [M+H]+. Anal. Found: C, 61.34; H, 3.29; N, 16.72%. Required for C21H13F4N5.0.05C4H8O2: C, 61.24; H, 3.25; N, 16.84%.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C>[C:8]([O:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(O)no1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)c2ccccc2)no1

Procedure:
3-Hydroxy-5-methylisoxazole was reacted with benzoyl chloride in the presence of triethylamine to give 3-benzoyloxy-5-methylisoxazole, which was then reacted with N-bromosuccinimide, to give 3-benzoyloxy-5-bromomethylisoxazole. This was reacted with disodium thioglycolate to give 3-hydroxyisoxazol-5-ylmethylthioacetic acid, which was treated with diphenyldiazomethane to give the benzhydryl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH2:16][CH2:17][CH3:18])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][C:10]=2[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:28][CH:29]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCCc1oc(-c2ccccc2Cl)nc1C(=O)O
Product: CCCc1oc(-c2ccccc2Cl)nc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 16 above, 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H25ClN4O3 (m/e) 428, obsd 429 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1COCC1>[N:20]1([CH2:2][C:3]2[CH:4]=[C:5]([NH2:12])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: Nc1cc(CBr)cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cc(CN2CCOCC2)cc([N+](=O)[O-])c1

Procedure:
A solution of 3-bromomethyl-5-nitrophenylamine (398 mg, 1.72 mmol), triethylamine (0.3 mL) and morpholine (0.2 mL) in 15 mL of THF was heated at 60° C. for 30 minutes. The solvent was evaporated in vacuo. The residue was mixed with water (20 mL) and extracted with ether. Organic layer was separated, dried over MgSO4 and concentrated in vacuo to afford a yellow solid (411 mg), which was purified by column chromatography. The title compound was isolated as yellow crystals in an amount of 302 mg (1.274 mmol, 74%); MS (m/z, ES+): 238 (M+1, 100%).
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=2)[C:11]=1[Cl:28])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C[CH2:30][OH:31].O>>[C:1]([C:3](=[CH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:31][CH3:30])[C:11]=1[Cl:28])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCO
Reactant: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2ccc(OC)cc2)c2ccccc12
Solvent: O
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2ccccc2OC)c2ccccc12

Procedure:
To 600 mg of 1-(2-methoxybenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 608 mg of potassium carbonate and 0.24 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (12a). Yield 630 mg of (12a). M.p. 126°-8° C. (sample recryst. from EtOH/water).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:24][C:22](=[CH2:23])[C:21]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)Oc1ccc(/C=C/C(=O)OC)cc1
Temperature: 15 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
10.5 g (59 mmol) of methyl 3-(4-hydroxy-phenyl)-acrylate were dissolved in 170 ml of tetrahydrofuran and treated in succession with 9.1 ml (65 mmol) of triethylamine and 0.079 g (0.65 mmol) of 4-dimethylamino-pyridine (DMAP). 6.8 g (65 mmol) of methacryloyl chloride were added dropwise to the solution, cooled to about 15° C., over a period of 30 minutes. The reaction batch was stirred at room temperature overnight and subsequently filtered over a thin silica gel layer. The silica gel layer was rinsed thoroughly with THF. After evaporation of the solvent the crude product was recrystallized from about 200 ml of ethanol. It was filtered off, dried and recrystallized once more from ethanol. Filtration and drying at 50° C. in a water-jet vacuum gave 10.3 g of 4-[(E)-2-methoxycarbonyl-vinyl]-phenyl 2-methyl-acrylate as white crystals with a melting point of 76-80° C. and an absorption maximum of λmax. (in CH2Cl2)=281.7 nm (ε=24290 l/mol cm).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH:9]=2)=[N:6][CH:7]=1.BrC1C=C(C)C(C2CCC(N3CCOCC3)CC=2)=[N:28]C=1>>[Si:15]([O:14][CH:11]1[CH2:12][CH2:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:28])=[CH:3][C:4]=2[CH3:22])=[CH:9][CH2:10]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Cc1cc(Br)cnc1C1=CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: Cc1cc(Br)cnc1C1=CCC(N2CCOCC2)CC1
Product: Cc1cc(N)cnc1C1=CCC(O[Si](C)(C)C(C)(C)C)CC1

Procedure:
5-Bromo-2-(4-{[tert-butyl(dimethyl) silyl]oxy}cyclohex-1-en-1-yl)-3-methylpyridine (8.4 g) was used inn place of 4-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]morpholine in Reference Example 108, and reacted and treated in a similar manner to give the titled compound (5.76 g) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>CO>[CH:11]1([NH:14][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CO
Product: c1nc(NC2CC2)c2nc[nH]c2n1
Yield: 153.1 %

Procedure:
A solution of 6-chloropurine (Aldrich Chemical Company, 4.23 g, 27 mmoles) and cyclopropylamine (Aldrich Chemical Company, 12.5 g, 22 mmoles) in MeOH (100 ml) was heated at 50° C. for 48 hours. The solvent was removed, and the crude product was purified on a silica gel column eluting with CHCl3 : 5% MeOH to obtain 5.90 g of a cream solid. This was recrystallized from MeOH to give two crops, 2.69 g and 1.16 g (81.4% total yield); mp. 237-240.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH:11][S:12]([C:15]1[CH:24]=[C:23]([NH:25][NH2:26])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([NH:11][S:12]([C:15]1[CH:24]=[C:23]([NH:25][N:26]=[C:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C1CCCC1
Reactant: COC(=O)c1ccc(NN)cc1S(=O)(=O)NC(C)(C)C
Solvent: CO
Product: COC(=O)c1ccc(NN=C2CCCC2)cc1S(=O)(=O)NC(C)(C)C
Temperature: 65 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
2.8 g (0.032 mol) of cyclopentanone are added to 2.0 g (0.007 mol) of methyl 2-(N-tert-butylsulfamoyl)-4-hydrazinobenzoate in 100 ml of methanol and the mixture is subsequently stirred at 65° C. for 3 hours. It is evaporated and the residue is triturated with a little methanol. After filtering off with suction and drying, 1.3 g (51% of theory) of methyl 2-(N-tert-butyl-sulfamoyl)-4-cyclopentylidenehydrazinobenzoate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O-])=[O:22])[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1.[Li+].[N:27]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:34][N:27]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CSc1c(C(=O)[O-])nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN1CCCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1c(C(=O)NN2CCCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 52 %

Procedure:
Compound 3 was prepared analogously as described for compound 2 hereinabove from crude lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate, azepan-1-ylamine, TBTU and Et3N in DMF in 52% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)(=[O:14])[CH3:13]
Reactant: COc1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2C(C)=O
Temperature: 60 °C
Yield: 91.8 %

Procedure:
To a solution 5-(methyloxy)-2,3-dihydro-1H-indole (8.9 g, 59.8 mmol, 1.0 eq) in acetic acid (120 mL) was added dropwise acetic anhydride (6.1 g, 59.8 mmol, 1.0 eq). The mixture was heated at 60° C. for 15 minutes. The reaction was quenched by pouring into water (100 mL). After cooling, a grey precipitate was formed, the precipitate was filtered by a Buchner funnel and rinsed with water to afford 1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indole (10.5 g, 91% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.13 (d, J=6.3 Hz, 1 H), 6.74-6.71 (m, 2 H), 4.05 (t, 2 H), 3.78 (s, 3 H), 3.17 (t, 2H), 2.21 (s, 3 H).
Reaction SMILES: O[CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:44]([CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1(c2ccc(COc3cccc(C(O)c4ccccc4)c3)cc2)CC1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1(c2ccc(COc3cccc(C(N=[N+]=[N-])c4ccccc4)c3)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a stirred solution of methyl 1-(4-((3-(hydroxy(phenyl)methyl)phenoxy)-methyl)phenyl)cyclopropanecarboxylate (1.824 g, 4.695 mmol) in toluene (21.8 mL) under an atmosphere of nitrogen, was added diphenylphosphoryl azide (1.21 mL, 5.635 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.84 mL, 5.635 mmol). The reaction mixture was stirred at 100° C. for 3 hours and then allowed to cool to room temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine and dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford a brown oil. The crude material was purified by silica gel chromatography eluting with 0-14% ethyl acetate in iso-hexane to afford the title compound as a colourless oil (1.214 g, 62%).
Reaction SMILES: N1C=CN=C1.[C:6]([O:9][CH:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([OH:22])[CH3:21])[CH2:11]1)(=[O:8])[CH3:7].[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C)C=O>[C:6]([O:9][CH:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([O:22][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH3:21])[CH2:11]1)(=[O:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O)[C@@]4(C)CC[C@@H]32)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
Imidazole (203.7 gm, 2.28 mol) was added to a stirred suspension of 3-acetoxy-pregn-5-ene-20-ol (361 gm, 1 mol) in dimethylformamide (3.7 L). t-Butyldimethylsilyl chloride (228.9 mg, 1.52 mol) was added over a 10-15 min period. The mixture was stirred at room temperature for 3 days. The dimethylformamide was removed by decantation and methanol (50 mL) was added to it. Water (4 L) was added and the solution extracted with ethyl acetate (2×4 L). The precipitant remaining behind after decantation was dissolved in ethyl acetate and added to the above ethyl acetate extracts. The combined solvent extracts were washed with water, saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was removed by rotoevaporation and the product purified by column chromatography on silica gel eluted with 2:1 hexane-methylene chloride followed by 1:1 hexane-methylene chloride. The title compound was isolated as a mixture of 20α- and _β-isomers (363.3 gm, 76% yield).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:18]([OH:20])[CH3:19])[CH:11]=[CH:10]1.N1C=CN=C1>O1CCCC1>[Si:1]([O:20][CH:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[NH:9][CH:10]=[CH:11]2)[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1cccc2cc[nH]c12
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1cccc2cc[nH]c12
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Add tert-butyldimethylsilyl chloride (16.4 g, 108 mmol) in anhydrous tetrahydro-furan (100 ml) to 1-(indol-7-yl)ethan-1-ol (10.7 g, 66.4 mmol) and imidazole (11.8 g, 173 mmol) in anhydrous tetrahydrofuran (100 ml). Stir at 20° C. for 2 hours. Dilute with hexanes (400 ml). Wash with 0.25 M aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with hexane containing 10-25% ethyl acetate to provide the desired compound (16 g, 87%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([C@@H:13]1[CH2:15][C@@H:14]1[F:16])[CH:10]=[C:9]([C:17]([O:19]CC)=[O:18])[C:8]2=[O:22])#[N:2].C(OC([NH:31][C:32]1([C@@H:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:34][CH2:33]1)=O)(C)(C)C.N12CCN(CC1)CC2>CS(C)=O>[NH2:31][C:32]1([C@@H:35]2[CH2:39][CH2:38][N:37]([C:4]3[C:3]([C:1]#[N:2])=[C:12]4[C:7]([C:8](=[O:22])[C:9]([C:17]([OH:19])=[O:18])=[CH:10][N:11]4[C@@H:13]4[CH2:15][C@@H:14]4[F:16])=[CH:6][CH:5]=3)[CH2:36]2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C#N)c(F)ccc2c1=O
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: N#Cc1c(N2CC[C@@H](C3(N)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
A mixture of ethyl 8-cyano-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate (250 mg, 0.785 mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (267 mg, 1.18 mmol), 1,4-diazabicyclo[2.2.2]octane (132 mg, 1.18 mmol), and dimethyl sulfoxide (13 ml) was stirred for 2 hours at room temperature under a nitrogen-replaced atmosphere. After evaporating the solvent, the residue was partitioned in chloroform (30 ml) and 10% aqueous citric acid solution (30 ml), and the organic layer was separated. The organic layer obtained was dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The residue was dissolved in concentrated hydrochloric acid (4 ml) and glacial acetic acid (4 ml) at room temperature and then stirred for 12 hours while heating in an oil bath at 110° C. After evaporating the solvent, concentrated hydrochloric acid (2 ml) and water (20 ml) were added, and the solution was transferred into a separation funnel and then washed with chloroform (50 ml). 10 mol/l Aqueous sodium hydroxide solution was then added to the aqueous layer after washing, thereby adjusting the pH to >12. Then after washing with chloroform (50 ml), the pH was adjusted to 8.3 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid. The aqueous layer obtained was then concentrated to 5 ml under a reduced pressure, subject to extraction into chloroform:methanol=10:1 (50 ml×3), and the combined organic layer was dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The yellow solids thus obtained were recrystallized in ethanol and then dried under a reduced pressure to obtain 124 mg (40%) of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH3:10][O:9][C:7](=[O:8])[CH2:6][N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:12]=1
Reactant: COC(=O)CN(CC(=O)OC)c1cccc(O)c1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Product: CCCCC/C=C\C/C=C\CCCCCCCCOc1cccc(N(CC(=O)OC)CC(=O)OC)c1

Procedure:
Using this procedure, the reaction of N-(3-hydroxyphenyl-N-(2-methoxy-2-oxoethyl)glycine methyl ester with linoleyl bromide gave N-(2-methoxy-2-oxoethyl)-N-[3-[(9Z,12Z)-(9,12-octadecadienyl]oxy]phenyl]glycine methyl ester as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([NH:60][CH2:61][C:62](O)=[O:63])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>>[C:50]([NH:60][CH2:61][C:62]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:63])([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.C1(P(Cl)([Cl:21])=O)C=CC=CC=1.C(OC(C)C)(C)C>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: CC(C)OC(C)C
Product: Clc1ncnc2ccc(I)cc12
Temperature: 150 °C

Procedure:
A mixture of 6-iodoquinazolin-4(3H)-one (Intermediate 11, 100 mg, 0.37 mmol) and phenylphosphonic dichloride (1.5 mL) was heated at 150° C. for one h. After cooling the reaction mixture in an ice bath, isopropyl ether was added. The resultant crystalline precipitate was collected by filtration, and was then stirred with saturated aqueous sodium bicarbonate solution. The solution was extracted with three portions of ethyl acetate, and the combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give the crude product. Purification by preparative thin layer chromatography (silica gel, 5% and 10% ethyl acetate/hexanes) afforded the desired product. LC/MS 291 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](SC)[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[S:19][CH:20]=2)[N:3]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[Cl-].[NH4+].C(OCC)(=O)C>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[S:19][CH:20]=2)[N:3]=1
Reactant: OC1CCNCC1
Reactant: CSc1c(C#N)c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c1C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCC(O)CC1

Procedure:
100 mg (0.23 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-(methyl-thio)pyridine-3,5-dicarbonitrile and 1000 mg (9.89 mmol) of 4-hydroxypiperidine are combined in 2 ml of acetone and stirred under reflux for 8 h. The mixture is then added to a mixture of semiconcentrated aqueous ammonium chloride solution and ethyl acetate. After vigorous mixing, the organic phase is separated off, washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered off using a glass frit, and the solvent is removed on a rotary evaporator. The residue is purified initially by column chromatography on silica gel 60 (mobile phase: gradient toluene/ethyl acetate 3:1→1:1) and then by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). The title compound in obtained as a white powder.