Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:35][CH2:36][F:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:37][CH2:36][CH2:35][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FCCBr
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(O)c3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(OCCF)c3)nc2c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (Example 80) (350 mg, 0.782 mmol) in DMF (5 ml) was added 1-bromo-2-fluoroethane (250 mg, 1.96 mmol) and K2CO3 (108 mg, 0.782 mmol). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (2×10 ml) and brine (15 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated off in vacuum. The crude material thus obtained was purified by column chromatography over silica gel (5% MeOH/DCM) to afford 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid {2-[3-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide as off-white solid (90 mg, 23%). LC-MS: m/z=494.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:18]1[CH2:27][CH2:26][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:19]1>CS(C)=O>[CH3:8][C:7]1[C:2]([N:18]2[CH2:27][CH2:26][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:19]2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: COC(=O)C1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1CCN(c2ncc([N+](=O)[O-])cc2C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-chloro-3-methyl-5-nitropyridine (1.73 g, 10.00 mmol) in DMSO (20 mL) was added sodium carbonate (5.30 g, 50.00 mmol) followed by methyl isonipecotate (1.35 mL, 10.00 mmol). The reaction mixture was heated to 60° C. for 110 minutes. The reaction mixture was left to stand at room temperature overnight. A further aliquot of methyl isonipecotate (3.33 mmol, 476 mg, 450 μL) was added and heating resumed at 60° C. for 100 mins. The reaction mixture was poured onto ice water and the suspension was filtered, washed with water (4×75 mL) and dried under vacuum to leave a yellow powder; (2.43 g, 87% yield). This was used in the next stage without further purification. 1H NMR δ 1.61-1.74 (m, 2H), 1.91-2.10 (m, 2H), 2.31 (s, 3H), 2.61-2.73 (m, 1H), 2.94-3.09 (m, 2H), 3.61 (s, 3H), 3.83-3.98 (m, 2H), 8.19 (d, 1H), 8.86 (d, 1H). MS m/e MH+ 280.18.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[H][H]>CO.[Pd].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CCCc1ccccc1)CCCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(CCCc1ccccc1)CCCc1ccccc1
Yield: 98 %

Procedure:
A solution of ethyl-2-(3-phenylpropyl)-5-phenyl-2-pentenoate in methanol (10 mL) was added to a suspension of 10% palladium on carbon (0.112 g) in methylene chloride (10 mL) and the mixture was hydrogenated under 60 psi of hydrogen for 6 h. The catalyst was removed by filtration through a pad of celite and the solvent was removed under reduced pressure to give ethyl-2-(3-phenylpropyl)-5-phenyl-pentanoate (0.787 g, 98%). The crude product was not purified further but used directly in the next step. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, 3 H, J=7.1), 1.60 (m, 8 H), 2.39 (m, 1 H), 2.61 (t, 4 H, J=7.3), 4.14 (q, 2 H, J=7.1), 7.24 (m, 10 H).
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].[CH3:8][Si:9]([CH3:23])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[CH:11]=[C:12](O)[CH:13]=[CH:14][CH:15]=1.S(OC)(OC)(=O)=O>O>[CH3:8][Si:9]([CH3:23])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[CH:11]=[C:12]([O:6][CH3:5])[CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCC[Si](C)(C)c1cccc(O)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCCCCC[Si](C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 0° C. slurry of 3.98 g. (0.166 mole) of sodium hydride in 50 ml. dimethylformamide was slowly added a solution of 26.1 g. (0.111 mole) of 3-(dimethyl-n-hexylsilyl)phenol in 50 ml. dimethylformamide. Following addition, the reaction mixture was stirred 1 hr at 25° C. and cooled to 0° C. To the cooled reaction mixture, 20.9 g. (0.166 mole) of dimethyl sulfate was slowly added. Following addition, the reaction was stirred for 2 hr at 25° C. and then added to 200 ml. water. The quenched reaction mixture was extracted with three 100 ml. portions of hexane. The hexane extract was dried over anhydrous magnesium sulfate and evaporated to an oil. This oil was purified by column chromatography on 500 g. of silica gel eluted with 1% diethyl ether hexane to yield 14.8 g. (53%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][C:29](=O)[CH2:30][C:31]1[NH:35][CH:34]=[N:33][N:32]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[NH:35][CH:34]=[N:33][N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CC1
Reactant: CCOC(=O)Cc1nnc[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3nnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CC1
Yield: 15 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclopropyloxy-4-methoxy-phenyl)-piperazine and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 7 days to afford the title compound as a yellow solid (20 mg, 15%). LC/MS (Method B) 3.12 min, [M+1]+ 448.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>C(#N)C>[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: COCCN
Solvent: CC#N
Product: COCCNCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), 2-methoxyethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 301 (M+, 2), 256 (19), 88 (bp), 56 (12), 58 (7).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40]/[CH:41]=[CH:42]/[CH3:43].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][C@H:41]1[C@H:42]([CH3:43])[C@H:16]2[C:15]1=[C:14]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:27])[N:13]1[C@H:12]([S:17]2)[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:38]1=[O:39]
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: C/C=C/C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)C2=C3[C@@H](C)[C@H](C)[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethyl-sulphonyloxy)ceph-3-em-4-carboxylate (40 mg, 0.0682 mmol) in dichloromethane (5.0 ml) was cooled to -20° C. Trans-2-butene (ca. 5 ml) was condensed into the solution. Diisopropylethylamine (12 μl, 0.068 mmol) was added and the mixture allowed to warm to room temperature over 1 h. The mixture was chromatographed to give the title compound (29.7 mg, 88%), m.p. 172°-173° C. (EtOAc) (Found: C, 65.6; H, 5.5; N, 5.6; S, 6.2; M+, 492.1724. C27H28N2O5S requires C, 65.8; H, 5.7; N, 5.7; S, 6.5%; M, 492.1719; νmax (CH2Cl2) 1786, 1721, 1687 cm-1 ; δH (CDCl3) 1.03 (3H, d, J 7.1), 1.25 (3H, d, J 7.3), 2.41 (1H, ddq, J 9.5, 7.1, 3.0), 3.04 (1H, ddq, J 7.3, 3.2, 3.0), 3.63 (2H, ABq, J 16.0), 3.79 (3H, s), 4.47 (1H, dd, J 9.5, 3.2), 4.90 (1H, d, J 4.9), 5.08 (1H, d, J 11.9), 5.26 (1H, d, J 11.9), 5.76 (1H, dd, J 9.0, 4.9), 6.07 (1H, d, J .9.0), 6.87 (2H, d, J 8.7), 7.30 (7H, m); δc (CDCl3), 15.9, 17.9, 37.2, 43.1, 43.4, 47.0, 55.3, 58.3, 59.8, 67.0, 114.0 (2c), 130.5 (2c) 121.7, 127.4, 127.7, 129.1 (2c), 129.5 (2c), 130.5 (2c), 133.8, 142.9, 159.8, 160.8, 164.2, 171.2
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:42]12([C:52](Cl)=[O:53])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]3)[CH2:43]1)[CH2:49]2>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:42]12([C:52]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:53])[CH2:49][CH:48]3[CH2:47][CH:46]([CH2:45][CH:44]([CH2:50]3)[CH2:43]1)[CH2:51]2.[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Into a mixture solution of 5.2 g (10 mmoles) of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-9, 1.1 g (11 mmoles) of triethylamine, 0.24 g (2 mmoles) of 4-dimethylaminopyridine, and 21 g of methylene chloride was added 5.5 g (11 mmoles) of a methylene chloride solution of adamantane-1-carbonyl chloride (40% by weight), and they were stirred at room temperature for 2 hours. Thereafter, the reaction was terminated by adding 12 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added methyl isobutyl ketone, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was washed by diisopropyl ether, and then dried to obtain the intended triphenylsulfonium 2-(adamantane-1-carbonyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (2.7 g of oily substance (yield 39%)). The structure of the intended product is shown below.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13](Cl)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Li+]>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccnc(-c2ccccc2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccnc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 145 mg of 2-phenyl-4-pyrimidinecarboxylic acid chloride in 5 mL tetrahydrofuran was added excess lithium borohydride. The reaction mixture was stirred at room temperature for 10 minutes then diluted with 25 mL of ethyl acetate and filtered. The filtrate was washed successively with 25 mL aliquots of 1N sodium hydroxide and brine. The solvent was removed by evaporation under reduced pressure to yield 100 mg of 2-phenyl-4-hydroxymethylpyrimidine as a white solid.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[CH2:17]([O:19][C:20](=[O:34])[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:24](=[O:32])[C:23]1=[O:33])[CH3:18].O1C2C=CC(O)=CC=2OC1.[CH3:45][C:46]1([CH3:56])[CH2:50][C:49]2[CH:51]=[CH:52][C:53]([OH:55])=[CH:54][C:48]=2[O:47]1>>[CH2:17]([O:19][C:20](=[O:34])[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([OH:32])([C:52]2[C:53]([OH:55])=[CH:54][C:48]3[O:47][C:46]([CH3:56])([CH3:45])[CH2:50][C:49]=3[CH:51]=2)[C:23]1=[O:33])[CH3:18]
Reactant: CC1(C)Cc2ccc(O)cc2O1
Reactant: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate and 1,3-benzodioxol-5-ol with 2,2-dimethyl-2,3-dihydrobenzofuran-6-ol, the title compound was obtained: MS (ES+) m/z 498.5 (M+23), 500.5 (M+23).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[H-].[Na+].C(O)(=O)C>CN(C=O)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccnc(F)c1
Reactant: Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccnc(Nc2ccc(F)cc2)c1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a mixture of 2-fluoro-isonicotinic acid (Aldrich, 423 mg, 3.0 mmol) and 4-fluoroaniline (555 mg, 5.0 mmol) in DMF (18 mL) at rt was added NaH (500 mg of 60% in oil), and the mixture was heated at 85° C. for 75 min. Acetic acid (0.7 mL) was added to the reaction mixture and it was concentrated in vacuo. To the residue were added EtOAc (100 mL) and water (20 mL), stirred for 20 min and the solid was filtered, washed with EtOAc and dried to obtain the desired product (600 mg, 50%) as a tan solid. 1H NMR (DMSO-d6) δ 8.98 (s, 1H), 8.43 (s, 1H), 8.04 (d, 1H, J=4.9 Hz), 7.69 (dd, 2H, J=8.8, 4.9 Hz), 7.24 (s, 1H), 7.05 (dd, 2H, J=8.2, 6.0 Hz); MS(ESI+) m/z 233.3 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:22]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=1
Reactant: COc1ccc(F)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Phenylacetic acid (8.09 g, 59.46 mmoles) was dissolved in 15 ml dichloromethane. To this mixture, oxalylchloride (5.2 ml, 59.46 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 15 ml dichloromethane. To this mixture, 4-fluoroanisole (5.0 g, 39.64 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (7.92 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (5.1 g, 56% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.43(s,1H), 7.77(dd, J=9.5,3.2Hz, 1H), 7.42(dt, J=8.7,3.2Hz, 1H), 7.33(t, J=7.3Hz, 2H), 7.26(m, 3H), 7.01(q, J=4.6 Hz, 1H),4.42(s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13](N(OC)C)=[O:14])[N:12]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.[NH4+].[Cl-]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH:10]=[C:11]([C:13]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:14])[N:12]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(c1ccc(F)cc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Yield: 69.5 %

Procedure:
To a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N-methyl-1H-imidazole-4-carboxamide (50.0 mg, 0.133 mmol) in 1.5 mL THE was added a 1.0 M solution of 4-fluorophenylmagnesium bromide (0.27 mL, 0.27 mmol) under argon at rt with stirring. The resultant mixture was stirred for 30 minutes and a saturated aqueous solution of NH4Cl was added. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated down in vacuo. The crude product was purified on HPLC to give [2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl](4-fluorophenyl)-methanone as a solid (38.0 mg, 69%): Rf=0.58 (1:1 ethyl acetate/hexanes).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]2=[O:3])=[CH:24][CH:23]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccccc21
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2ccccc21
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 367 mg) in N,N-dimethylformamide (15 ml) was added a solution of ethyl 2-(1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (2.0 g) in N,N-dimethylformamide (35 ml) with stirring at room temperature under nitrogen atmosphere, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-chlorobenzyl chloride (1.48 g) with stirring at room temperature and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated in vacuo to give a residue, which was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried. Evaporation of the solvent gave a residue, which was washed with n-hexane to afford ethyl 2-[3-(4-chlorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (2.55 g).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.C([O-])(=O)C.[Na+].[Cl-].O[NH3+:23].C(O)(=O)C>O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)#[N:23]
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)Cc1ccccc1-2
Yield: 63.3 %

Procedure:
25 g of 2-fluorenecarboaldehyde, 11.6 g of sodium acetate, 9.7 g of hydroxy ammonium chloride and 150 ml of acetic acid were stirred at 130 for 18 hours. The reaction mixture was allowed to room temperature, poured into 200 ml of water and the precipitate was collected by filtration. The crude product was purified by column chromatography, giving 15.57 g (63%) of 2-cyanofluorene.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][CH2:5][C@H:4]1[OH:8].Cl[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C(=O)(O)[O-].[Na+]>O>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[N:6]1[CH2:7][C:3]([CH3:9])([CH3:2])[C@H:4]([OH:8])[CH2:5]1
Reactant: CC1(C)CNC[C@H]1O
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)CN(c2nc3ccccc3s2)C[C@H]1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a slurry of 600 mg (4 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 670 mg (4 mmol) of 2-chlorobenzthiazole was added a solution of 1.0 g (12 mmol) of sodium bicarbonate in water. The reaction mixture was heated to 80° C. and stirred overnight. It was then diluted with water, the resulting mixture was extracted with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 950 mg (96%) of (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethyl-3-pyrrolidinol. 1H-NMR (300 MHz, DMSO-6): δ 7.76 (d, J=8 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.04 (t, J=8 Hz, 1H), 5.27 (d, J=5 Hz, 1H), 3.84–3.77 (m, 2H), 3.39–3.25 under DMSO peak (m, 3H), 1.05 (d, J=8 Hz, 6H); ES-LCMS m/z 249 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2cccc(C)c2o1
Reactant: Brc1ccccn1
Product: Cc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 54.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (26 mg, 0.16 mmol) and 2-(but-3-ynyl)-7-methyl benzo[d]oxazole (30 mg, 0.16 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 23 mg (87 μmol, 54%) of 7-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O:17]CC)=[O:16])[C:3]1=[O:20].[Li+:21].[OH-].Cl>C1COCC1.O>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O-:17])=[O:16])[C:3]1=[O:20].[Li+:21]
Reactant: CCOC(=O)CN1C(=O)[C@@H](C)OC[C@H]1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1OC[C@@H](c2ccccc2)N(CC(=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(2R,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate from Step C (590 mg, 2.13 mmol) in THF (5 mL) and H2O (5 mL) was added 1 N aqueous LiOH (2.55 mL, 2.55 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=250 (M+1).
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>CO>[OH:1][CH:2]([CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NOCC1CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NOCC(O)CN1CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
A 150 mg (0.79 mmol) portion of tert-butyl N-(2,3-epoxypropoxy)carbamate was dissolved in 1 ml of methanol, and the solution was mixed with 0.08 ml (0.95 mmol) of pyrrolidine and stirred at room temperature for 14 hours. The reaction solution was mixed with a saturated ammonium chloride aqueous solution and extracted with chloroform. The chloroform layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 181 mg (yield, 88%) of tert-butyl N-(2-hydroxy-3-pyrrolidinylpropoxy)-carbamate.