Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:20]([C:24]1[S:31][C:30]2[C:29](=[O:32])[N:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35](B4OC(C)(C)C(C)(C)O4)[C:34]=3[CH3:48])[CH2:27][C:26]=2[CH:25]=1)([CH3:23])([CH3:22])[CH3:21].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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:20]([C:24]1[S:31][C:30]2[C:29](=[O:32])[N:28]([C:33]3[C:34]([CH3:48])=[C:35]([C:2]4[CH:3]=[C:4]([NH:9][C:10]5[CH:19]=[C:13]6[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]6[N:11]=5)[C:5](=[O:8])[NH:6][N:7]=4)[CH:36]=[CH:37][CH:38]=3)[CH2:27][C:26]=2[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)[nH]n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 25 °C

Procedure:
In a dried pressure flask was placed 0.968 mmol of 101m, 1.065 mmol of 101g, and 56 mg (5 mol %) of tetrakis(triphenylphosphine)palladium(0), The flask was evacuated under vacuum, then filled with nitrogen. This procedure was repeated twice more, then 8 mL of anhydrous dioxane and 2.4 mL (2.5 equivalents) of 1 M aqueous sodium carbonate solution were added, and the mixture was heated at 100° for 18 h. The mixture was cooled to room temperature, then diluted with ethyl acetate, washed with saturated aqueous saturated NaCl solution four times, dried over anhydrous Na2SO4, and purified by chromatography on a Biotage 25M KP NH column to afford 101. 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 9.19 (s, 1H), 7.78 (s, 1H), 7.54-7.32 (m, 3H), 7.15 (s, 1H), 5.97 (s, 1H), 4.78 (s, 2H), 3.97 (t, J=5.3, 2H), 3.52 (s, 2H), 2.80 (t, J=5.4, 2H), 2.36 (s, 3H), 2.11 (d, J=12.1, 3H), 1.42 (s, 9H). ESIMS m/z=530.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 50 °C
Yield: 68.9 %

Procedure:
To 3-nitrobenzene-1-sulfonyl chloride (296.9 mg, 1.340 mmol) is added THF (20 mL), aniline (134.8 mg, 1.447 mmol) and potassium carbonate (408.5 mg, 2.955 mmol). The resulting mixture is heated at 50° C. for 16 hours. The reaction mixture is subsequently cooled and concentrated in vacuo after which the residue is treated with 10 ml of H2O and extracted with EtOAc (75 mL). The organic layer is washed with saturated aqueous NaCl (2×75 mL), dried (MgSO4), and concentrated in vacuo. The residue is purified over silica (CH2Cl2) to afford 257 mg (69% yield) of the desired compound. MS (ESI, pos. ion) m/z: 279 (M+1).
Reaction SMILES: [CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[CH:50]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[O:48][N:47]=1>>[C:51]([C:49]1[O:48][N:47]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[CH:50]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)on5)c5ccccc54)cn23)CC1)(C(C)C)C(C)C

Procedure:
Intermediate 14e was reacted with (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (WO 2006/091671, which is incorporated herein by reference in its entirety) in an analogous manner to that described in Example 14 step f to give the title compound. LCMS (Method 3): Rt: 5.43 min, m/z 717 [MH+].
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=CC=1)(O)=O.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:11]([N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:21]([CH2:14][CH2:13][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:22][CH:23]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:22][CH2:23][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:29]=2[CH2:30]1)[CH3:10]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: C1CCNCC1
Product: CCN(Cc1ccc(CCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 51.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (27 mg) and piperidine (14 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (6.6 mg) was obtained.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1>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:1]1([C:11]2[S:12][CH:13]=[C:14]([Br:16])[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Brc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A flask containing 238 mg of tetrakis(triphenylphosphine)palladium, 0.55 g of phenylboronic acid, and 1.00 g of 2,4-dibromothiazole was purged with nitrogen and then charged with 30 ml of toluene, 6.1 ml of ethanol, and 9.1 ml of a 2 M aqueous solution of sodium carbonate, and the mixture was stirred under reflux for 6 hours. After cooling to room temperature, 50 ml of water was added to the reaction mixture and two extractions were conducted with 50 ml of ethyl acetate. After being washed with 30 ml of saturated brine, the organic layer was dried over magnesium sulfate. After filtering the magnesium sulfate, the organic layer was concentrated and the residue was purified by column chromatography (Wakogel C-200; hexane:ethyl acetate=14:1) to give 0.71 g of 2-phenyl-4-bromothiazole.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[O:19]C)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.Br>C(O)(=O)C>[CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:12]=[CH:11][C:10]=2[OH:19])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)C1CCCCC1
Agent: Br
Agent: I
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(O)c(C(=O)C2CCCCC2)c1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
To 1.70 g of 2-cyclohexylcarbonyl-4-tert-butylanisole [prepared in Reference Example 2 (a)] dissolved in 10 ml of glacial acetic acid were added 1.0 ml of 57% hydroiodic acid and 2.0 ml of 47% hydrobromic acid, and heated at reflux for 2 hours. The reaction mixture was poured into 50 ml of ice-water, extracted with diethyl ether, and the extract was washed with saturated aqueous sodium thiosulfate solution, water and saturated brine successively, dried over magnesium sulfate anhydride and concentrated at reduced pressure. The residue was chromatographed on silica gel column using a mixed solvent of methylene chloride and cyclohexane (1:2) as an eluting agent to give 1.54 g of the title compound having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[CH3:26]I>O1CCCC1>[Br:1][C:2]1[C:3]([NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([O:23][CH3:26])[CH2:21][CH2:22]2)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: CI
Reactant: Cc1nc(-n2c(C)ccc2C)nc(N[C@H]2CC[C@H](O)CC2)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](Nc2nc(-n3c(C)ccc3C)nc(C)c2Br)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a cooled (0° C.) solution of trans-4-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-ylamino)cyclohexanol (1.45 g, 3.82 mmol) in tetrahydrofuran (40 mL) was added sodium hydride (60% dispersion in oil, 459 mg, 11.5 mmol). After 40 minutes, methyl iodide was added (262 uL, 4.21 mmol) and the mixture was stirred at 0° C. for 2 hours. The ice bath was removed and continued to stir for 3 hours then quenched with methanol and concentrated. The residue was dissolved in ethyl acetate and washed with saturated ammonia chloride (2×), brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with hexanes/methyltertbutyl ether (5-25%) to afford 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(trans-4-methoxycyclohexyl)-6-methylpyrimidin-4-amine (1.10 g, 73%).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)(=O)=O)=CC=1.[CH3:31][O:32][CH:33]1[CH2:37][O:36][CH2:35][CH:34]1O>>[CH3:31][O:32][C@H:33]1[CH2:37][O:36][CH2:35][C@H:34]1[O:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: COC1COCC1O
Product: CO[C@H]1COC[C@H]1OCCOC1CCNCC1
Yield: 84.8 %

Procedure:
Using benzyl 4-(2-{[(4-methylphenyl)sulfony]oxy}ethoxy)piperidine-1-carboxylate (2.50 g, 5.77 mmol) produced in Reference Example 1 (1c) and 4-methoxytetrahydrofuran-3-ol (820 mg, 6.94 mmol), the desired title compound (1.20 g, yield 85%) was obtained by the same method as in Reference Examples 1 (1d) and 1 (1e).
Reaction SMILES: [CH2:1]([C:5]1[CH2:9][CH2:8][C:7](=[N:10][OH:11])[C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([F:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.CCCCCC>[CH2:1]([C:5]1[CH2:9][CH2:8][C:7](=[N:10][OH:11])[C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=C(c2ccc(OC)c(F)c2)C(=NO)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC1=C(c2ccc(O)c(F)c2)C(=NO)CC1
Reaction time: 2 h
Yield: 57.9 %

Procedure:
To a stirred solution of 20 mg 3-butyl-2-(3-fluoro-4-methoxyphenyl)-2-cyclopenten-1-one oxime (Example 40) in 5 ml dichloromethane, was added 0.5 ml 1.0 M boron tribromide in hexane at 0° C. under inert atmosphere. The reaction mixture was stirred for 2 hours, poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Then the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=2:1) to yield 11 mg 3-butyl-2-(3-fluoro-4-hydroxyphenyl)-2-cyclopenten-1-one oxime. Spectral data for Example 41 are provided along with the melting point in Table 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:17]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:10]([CH3:17])[C:11](=[O:13])[CH3:12])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)N[C@H](C)c1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N(C)[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a vial is added N-[(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-acetamide (111 mg, 0.46 mmol) in 3 ml of THF, followed by the addition of 60% NaH (35 mg, 0.92 mmol). Then iodomethane (130 mg, 0.91 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 103 mg of N-[(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-N-methyl-acetamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:25][C:24]3[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=[CH:22][C:23]=3[CH3:27])=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(C)c(N)c1
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc(C)c(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Temperature: 115 °C
Yield: 62.1 %

Procedure:
A mixture of 0.9 g (3.36 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 0.55 g (4.0 mmol) of 5-methoxy-2-methylaniline, 0.46 g (4.0 mmol) of pyridine hydrochloride in 10.0 mL of 2-ethoxyethanol is heated at 115° C. for 1 hour, cooled and poured into a saturated solution of sodium bicarbonate. The oil is extracted with methylene chloride, dried over anhydrous sodium sulfate and the solvent is evaporated to yield a foam. This is purified by silica gel chromatography, eluting with methylene chloride/methanol (99.5:0.5) to yield 0.77 g of 7-chloro-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile as a yellow solid, mp 180–182° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[CH3:22][N:23]([CH3:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:28]
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CN(C)c1cccc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 46 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-(dimethylamino)benzoyl chloride and conditions outlined in procedure N. M.p.=170-172° C.; LCMS: 449 [M+H].
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[N:9][C:10]2[N:11]([N:13]=[C:14]([CH3:16])[CH:15]=2)[CH:12]=1.CN([CH:20]=[O:21])C>>[Br:6][C:7]1[CH:8]=[N:9][C:10]2[N:11]([N:13]=[C:14]([CH3:16])[C:15]=2[CH:20]=[O:21])[CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1cc2ncc(Br)cn2n1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn2cc(Br)cnc2c1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
POCl3 (1.84 mmol, 1.3 eq, 172 μl) is added dropwise to DMF (1 ml) at 0° C. and the resulting solution is stirred at 0° C. during 30 minutes. Then, a solution of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine x14 (1.415 mmol, 1 eq, 300 mg) in DMF (1 ml) is added and the mixture is stirred for 30 minutes at room temperature. The reaction is quenched with water (100 ml). The resulting solid is filtered and washed with water to give 200 mg of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x21 as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[CH:30]1([NH:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNC4CCCCC4)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15g) and cyclohexylamine (0.17ml) in dimethylformamide (10ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanolhexane to give N-(4-((cyclohexylamino)methyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 114) (0.09g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:5]2[CH:12]=[CH:13][C:14]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:4]=2[N:3]=1.Cl.[C:25](=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]([O:11][CH3:25])=[O:10])[C:5]2[CH:12]=[CH:13][C:14]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:4]=2[N:3]=1
Reactant: O=C([O-])O
Reactant: Nc1nc2cc(C(=O)c3ccccc3)ccc2n1CCC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCn1c(N)nc2cc(C(=O)c3ccccc3)ccc21
Reaction time: 16 h

Procedure:
A solution of 3-(2-amino-5-benzoylbenzimidazol-1-yl)-propionic acid (6.1 g.) in methanol (30 ml.) was treated with a saturated solution (30 ml.) of hydrogen chloride in methanol. The mixture was left at room temperature for 16 hours and then evaporated. The residue was dissolved in water. The solution obtained was adjusted to pH 8.5 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3×50 ml.). The extracts were dried (MgSO4) and evaporated to give methyl 3-(2-amino-5-benzoylbenzimidazol-1-yl)propionate as an oil. This oil was dissolved in methanol (60 ml.) and the solution heated at reflux for 5 hours. The solid which precipitated was collected and washed successively with methanol, acetone and then ether to give 8-benzoyl-3,4-dihydropyrimido[1,2-a]-benzimidazol-2(1H)-one (3.4 g.), m.p. 323°-330° C., microanalysis, C17H13N3O2 requires: C, 70.1; H, 4.5; N, 14.4% found: C, 69.9; H, 4.4; N, 14.0%.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:18]/[C:19](/[CH3:26])=[CH:20]/C(OCC)=O)C>>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[CH3:14])=[CH:20]/[C:19](=[O:18])[CH3:26])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: CCOC(=O)/C=C(\C)OCC
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCC2)cc1
Yield: 55 %

Procedure:
(E)-4-(4-cyclohexyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 4'-cyclohexyl-acetophenone and ethyl (E)-3-ethoxy-crotonate with a yield of 55% of theory. B.p. 148°-151°C at 0.4 mm Hg; m.p. 49°-50°C (after recrystallization from methanol and petroleum ether). Characteristic signals in NMR (CDCl3): τ 3.50 (1H-q; /J/=1.2 ± 0.1 Hz); τ 7.50 (3H-d; /J/=1.2 ± 0.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]([CH3:16])[O:13][C:12]1=[O:17].[H][H]>[Pd].O1CCCC1>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:15][CH:14]([CH3:16])[O:13][C:12]2=[O:17])=[C:2]([Cl:1])[CH:7]=1
Reactant: [H][H]
Reactant: CC1CN(c2ccc([N+](=O)[O-])cc2Cl)C(=O)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1CN(c2ccc(N)cc2Cl)C(=O)O1

Procedure:
A solution of 16.5 g of 2B and 0.5 g of 10% palladium-on-carbon catalyst in 200 ml of tetrahydrofuran was treated with hydrogen in a Parr shaker, giving 3-(4-amino-2-chlorophenyl)-5-methyl-2-oxazolidinone (2C), as a white solid, mp: 140°-141° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12].Cl>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[OH:13][CH2:9][CH2:10][C:11]#[C:12][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[C:11][CH2:10][CH2:9][OH:13])=[CH:4][CH:3]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
First, 16.5 g of p-diiodobenzene and 8.0 g of 3-butyn-1-ol were dissolved in 200 ml of triethylamine, 0.35 g of bis(triphenylphosphine)palladium (II) chloride and 0.19 g of cuprous iodide were added thereto, and the reaction mixture was stirred under nitrogen gas flow at a room temperature for 3 hours. After the reaction was completed, an insoluble matter was filtered off and the filtrate was evaporated under a reduced pressure. To the residue was added a small amount of ethyl acetate, which was then evaporated under a reduced pressure. To the residue was added water, and the mixture was extracted with 100 ml of ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. On the other hand the insoluble matter obtained above was acidified with 1N HCl and extracted with 100 ml of ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. This ethyl acetate layer was combined with the ethyl acetate layer obtained above, and the mixture was evaporated under a reduced pressure to obtain 10.2 g of 1,4-bis(4-hydroxy-1-butynyl)benzene as a yellow residue.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([O:17]CC1C=CC=CC=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([OH:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OC)c2cc(OCc3ccccc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(OC)c2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 12 h
Yield: 83.3 %

Procedure:
5% Pd/C (100 mg) was added to a stirred solution of ethyl-N-(3,4-dichlorobenzyl)3-methoxy-5-benzyloxyindole-2-carboxylate (0.9 g) in ethyl acetate (50 ml) and the mixture was hydrogenated for 12 hours. Catalyst filtered off and filtrate evaporated to give a brown oil (0.61 g) which was used without further purification. NMR: δ 1.4 (t, 3H), 4.0 (s, 3H), 4.4 (q, 2H), 5.6 (s, 2H), 6.8 (dd, 1H), 6.9 (dd, 1H), 7.1 (m, 3H), 7.3 (d,1H); m/z 394 (MH+)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: COC(=O)CCc1ccc(N)cc1
Product: COC(=O)CCc1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1
Yield: 84 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (90 mg, 0.459 mmol) was condensed with methyl 3-[4-aminophenyl]propionate, and the resultant was purified by silica gel chromatography [benzene-ethyl acetate (14:1)] to obtain methyl 3-[4-[(4,5-diisopropylfuran-2-carbonyl)amino]phenyl]propionate (138 mg, 84%) as colorless needles.