Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.N1C=CC=CC=1.CS([Cl:33])(=O)=O>ClCCl>[Cl:33][C:7]1[CH:6]=[C:5]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Cl)cc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.7 %

Procedure:
To a 0° C. solution of 3-chloro-5-methoxy-phenol (Scheme #4, K) (16.62 g, 104.80 mmol) and pyridine (12.8 mL, 157.20 mmol) in dichloromethane (150 mL) was added methanesulfonyl chloride (8.9 mL, 115.28 mmol). The reaction was warmed to room temperature and stirred 24 hours. The dichloromethane was removed under reduced pressure and the crude material partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed 1N hydrochloric acid (4×), aqueous saturated sodium chloride (1×), saturated potassium carbonate (3×), aqueous saturated sodium chloride (1×), dried over magnesium sulfate, and solvent removed under reduced pressure. The crude solid was crystallized overnight from dichloromethane (50 mL) and crystals filtered off, washed with dichloromethane, and placed under high vacuum to give the title compound (9.35 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ 7.09 (t, J=2.0 Hz, 1 H), 7.05 (t, J=1.9 Hz, 1 H), 6.93 (t, J=2.1 Hz, 1 H), 3.82 (s, 3 H), 3.42 (s, 3 H); MS (APCI+) m/z 237 [M+1]+; tR=2.28 min.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.O>CS(C)=O>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:12]2([CH3:11])[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:30][CH:29]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: O
Product: CC1(NCc2ccc(F)cc2)COc2ccc3c(c2O1)CC(=O)N3
Temperature: 85 °C
Yield: 61.5 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.15 g, 3.07 mmole) and 4-fluorobenzylamine (1.56 ml, 13.6 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 0.75% methanol/CH2Cl2 as eluant. The free base of the title compound (0.62 g, 62%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.69 g of the (S) enantiomer of the title compound as an off-white solid fumarate, m.p. 218°-220° C.
Reaction SMILES: ClCCl.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([Cl:17])=[C:11]([S:13](Cl)(=[O:15])=[O:14])[CH:12]=1)([O-:6])=[O:5].[CH3:18][NH: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][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(N(CC)CC)C>[CH3:18][N: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][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[S:13]([C:11]1[CH:12]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=[CH:9][C:10]=1[Cl:17])(=[O:15])=[O:14]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
Dichloromethane (100 ml) was mixed with 44 grams of 5-nitro-2-chlorobenzenesulfonyl chloride and a dichloromethane solution which contained 48.4 grams of methyloctadecylamine and 36.1 ml of triethylamine was added dropwise to the mixture. After the reaction had been completed the reaction solvent was removed by distillation under reduced pressure, 300 ml of methanol was added and a solution was formed by heating. Crystals precipitated out on cooling the solution slowly and these were recovered by filtration and dried.
Reaction SMILES: [K].CC(O)(C)C.[CH2:7]([N:14]([CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)[CH2:15][CH2:16][CH2:17]C(OCC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1(C)C(C)=CC=CC=1>[CH2:7]([N:14]1[CH2:15][CH2:16][CH2:17][C:26](=[O:28])[CH2:25][CH2:24][CH2:23]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCN(CCCC(=O)OCC)Cc1ccccc1
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1C
Solvent: CC(C)(C)O
Product: O=C1CCCN(Cc2ccccc2)CCC1

Procedure:
To a stirred boiling slurry made from potassium (1.28 g, 32.8 mmol) and t-BuOH (2.43 g, 32.8 mmol) in xylene (182.5 mL) under N2 was added diethyl 4,4′-(benzylazanediyl)dibutanoate (O2) (5 g, 14.9 mmol) over 5 hrs in xylene (37.25 mL). The mixture was stirred and heated at reflux for 1 hr. After being cooled, the reaction mixture was neutralized with 6N HCl (100 mL) and then was extracted with 6N HCl (3×50 mL). The combined acid solutions were filtered and the filtrate was heated under reflux for 1 hr. After cooling, the mixture was basified with concentrated KOH solution to pH 10 with cooling and extracted with dichloromethane. The combined organics were dried over Na2SO4 and concentrated to give a residue. Another 17 batches were done in parallel. The combined residue from 18 batches was purified together by column (P.E./EtOAc 5:1) to give 1-benzylazocan-5-one (O3). 1H NMR (CDCl3, 400 MHz) δ 7.30-7.33 (m, 2H), 7.21-7.25 (m, 3H), 3.56 (s, 2H), 2.55 (t, J=6.0, 4H), 2.24 (t, J=6.4 Hz, 4H), 1.86-1.91 (m, 4H).
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][C:7]#[N:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.P([S-])(OCC)(OCC)=[S:16]>Cl.C(OCC)(=O)C>[C:4]1(=[O:9])[N:5]([CH2:6][C:7]([NH2:8])=[S:16])[C:1](=[O:14])[C:2]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:3]12
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Reactant: CCOP(=S)([S-])OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=S)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 20 ml 4N solution of hydrogen chloride in ethyl acetate, 3.07 g of phthalimidoacetonitrile was dissolved. To the resulting solution, 3.17 ml of O,O-diethyl dithiophosphate was added, followed by stirring at room temperature for 6 hours. The precipitate formed was collected by filtration, and washed successively with ethyl acetate and diethyl ether, whereby 2.29 g of phthalimidothioacetamide was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10]1([C:16](O)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:16]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:17])=[N:6][CH:7]=1
Reactant: O=C(O)C1CCCCC1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Product: O=C(NNc1ccc(F)cn1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010 022076, which is incorporated herein by reference in its entirety; 1.00 g, 7.87 mmol), cyclohexane carboxylic acid (1.21 g, 9.44 mmol), and HOBt.H2O (166 mg, 0.787 mmol) at 0° C. under N2 was added EDC (1.81 g, 9.44 mmol), then the mixture stirred at 0° C. for 15 min, and at RT for 17 h. Water was added, then the organics isolated, cooled to 0° C., then the resulting suspension filtered to leave the title compound as a white solid (1.16 g, 62%). 1H NMR (400 MHz, CDCl3): 1.21-1.38 (3H, m), 1.45-1.55 (2H, m), 1.66-1.73 (1H, m), 1.80-1.96 (4H, m), 2.22 (1H, tt, J 11.6, 3.5 Hz), 6.62-6.66 (2H, m), 7.29 (1H, ddd, J 9.2, 7.9, 3.1 Hz), 7.55 (1H, d, J 4.2 Hz), 8.03 (1H, d, J 2.9 Hz).
Reaction SMILES: C([O:8][C:9](=[O:31])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:24](=[O:30])[N:25]([CH2:27][CH2:28][OH:29])[CH3:26])[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.[Pd]>[OH:29][CH2:28][CH2:27][N:25]([CH3:26])[C:24]([CH:19]([C:20]([O:22][CH3:23])=[O:21])[O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([OH:31])=[O:8])=[CH:13][CH:14]=1)=[O:30]
Reactant: COC(=O)C(Oc1ccc(CCC(=O)OCc2ccccc2)cc1)C(=O)N(C)CCO
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Oc1ccc(CCC(=O)O)cc1)C(=O)N(C)CCO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(4-{[(2-hydroxy-ethyl)-methyl-carbamoyl]-methoxycarbonylmethoxy}-phenyl)-propionic acid benzyl ester (step 3) (0.44 g, 1.02 mmol) in MeOH (20 ml) was treated with palladium on activated carbon (10% wt, 50 mg, 0.047 mmol) and stirred under an atmosphere of hydrogen for 20 h at RT. The reaction mixture was filtered through Celite® (filter material) and washed through with EtOAc. The filtrate was concentrated in vacuo and purification of the crude product by chromatography on silica eluting with 0-10% MeOH in DCM afforded the title compound; LC-MS: 340.2 [M+H]+
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[N:7]2)(=[O:32])=[O:33])=[CH:29][CH:30]=1
Reactant: c1ccc2c(C3CCCC3)n[nH]c2c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)n2nc(C3CCCC3)c3ccccc32)cc1
Reaction time: 12 h
Yield: 45.7 %

Procedure:
Combine 3-Cyclopentyl-1H-indazole (2.168 g 11.640 mmole) with triethylamine (3.526 g, 34.92 mmoles) in 50 mls of dichloromethane. Dissolve 4-Chlorosulfonyl-benzoic acid methyl ester (4.085 g, 17.460 mmole) in dichloromethane 50 ml and add drop wise to solution at 0° C. Stir the reaction is for 12 hrs. Dilute the reaction and wash with NaHCO3. Dry organic layer over MgSO4 and concentrate. Purify the residue via column chromatography with a mixture of ethyl acetate and hexanes to isolate 2.046 g (Yield=48.5%) of the title compound: MS ES+ 385.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:27])[C@H:15]([NH:23][C:24](=[O:26])[CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH:29]([CH3:35])[CH2:30][CH2:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][CH2:30][CH:29]([CH3:35])[CH3:28])[CH2:10][C@@H:9]1[C@@H:14]([OH:27])[C@H:15]([NH:23][C:24](=[O:26])[CH3:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N[C@H](Cc1ccccc1)[C@H](O)[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](Cc1ccccc1)[C@H](O)[C@H]1CN(C(=O)CCC(C)C)CCN1C(=O)OC(C)(C)C
Yield: 48.6 %

Procedure:
Dissolve 2-(R)-(2-(R)-Acetylamino-1-(S)-hydroxy-3-phenyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (122 mg, 0.32 mmol) in 3 ml of dry CH2Cl2. Add 4-methylpentanoic acid (0.04 ml, 0.32 mmol), EDCI (73.6 mg, 0.38 mmol), HOBT (51.8 mg, 0.38 mmol), triethylamine (0.13 ml, 0.96 mmol) and dimethylaminopyridine (3.9 mg, 0.032 mmol), and stir at room temperature overnight. Dilute with CH2Cl2, and wash with 5% NaHCO3 followed by saturated aqueous sodium chloride. Dry organic layer with MgSO4 and remove the solvent under reduced pressure. Subject residue to silica gel chromatography, eluting with ethyl acetate/methanol 9:1 to obtain 74 mg (48% yield) of a white solid.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1>>[CH3:12][C@H:13]1[NH:14][C@@H:15]([CH3:19])[CH2:16][N:17]([C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=O)[nH]1
Yield: 73.7 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (1.00 g, 6.53 mmol) reacted with cis-2,6-dimethylpiperazine (900 mg, 7.84 mmol) to give 1.2 g (74%) of 3-[(3R,5S)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCOCC1.ClCCl>[CH2:14]([O:21][C:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Aminomethyl)benzoic acid 15.1 g (100 mmol) was dissolved in 200 mL dioxane and 100 mL 1.000 N NaOH and cooled in a 0° C. ice bath. The mixture was treated dropwise with benzylchloroformate 14.3 mL (100 mmol) followed by the dropwise addition of 100 mL of 1.000 N NaOH. The mixture was stirred at room temperature for 18 hours. The mixture was neutralized by adding 100 mL of 1.000 N HCl followed by dilution with dichloromethane. A white solid precipitated out which was filtered. The solid was dried in vacuo to afford 10.8 g (38.9%). 1H NMR (300 MHz, DMSO-d6): δ 4.24 (d, 2H, J=6.2 Hz); 5.01 (s, 2H); 7.31-7.34 (m, 7H); 7.84-7.88 (m, 3H); 12.85 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:36][CH2:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NCCCN1CCOCC1
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCCN3CCOCC3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and N-(3-aminopropyl)morpholine employing methods similar to those described in Example 5 and was obtained as a white solid: 1H NMR (CDCl3) δ 13.29 (1H, br), 10.31 (1H, t, J=6 Hz), 8.62 (1H, d, J=1 Hz), 7.82 (2H, d, J=8.3 Hz), 7.30 (3H, m), 7.18 (2H, d, J=8.3 Hz), 7.07 (1H, s), 7.03 (2H, m), 5.40 (2H, br), 4.32 (2H, m), 4.06 (2H, s), 3.97 (2H, m), 3.60 (2H, m), 3.46 (2H, m), 3.08 (2H, m), 3.02 (3H, s), 2.87 (2H, m), 2.34 (2H, m); HRMS calcd for C31H34N4O6S+H+: 591.2277. Found: 591.2277.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[O:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[O:24][C:25]([CH3:28])=[CH:26][CH:27]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: Cc1ccc(-c2nc(CCl)co2)o1
Product: Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)o1
Yield: 94 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-methyl-2-furyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-furyl)oxazole. The yield was 94%. Recrystallization from ethyl acetate-isopropyl ether gave colorless prisms, mp 109-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].Cl>N1CCCCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)O)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of 3,4-dimethoxybenzaldehyde (5.0 g, 30 mmol) and malonic acid (4.7 g, 45 mmol) in a mixture of piperidine (0.5 mL) and pyridine (15 mL) was heated to 120° C. and stirred overnight. The mixture was cooled to rt and acidified with conc. HCl. The resulting precipitate was filtered and washed with water to give (E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid (5.1 g, 81%) as a pale brown solid; δH (400 MHz, DMSO-d6) 3.78 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 6.42 (d, J=16.0 Hz, 1H, CH═CHCO2H), 6.96 (d, J5,6=8.0 Hz, 1H, H5), 7.19 (d, J5,6=8.0 Hz, 1H, H6), 7.30 (s, 1H, H2), 7.51 (d, J=16.0 Hz, 1H, CH═CHCO2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Br:13])[CH:3]=1.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([SH:27])=[CH:22][C:21]=1[CH3:28])[CH3:15].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27][C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Br:13])[CH:3]=2)=[CH:22][C:21]=1[CH3:28])[CH3:15]
Reactant: CCOC(=O)COc1cc(C)c(S)cc1C
Reactant: CC(C)COc1cc(Br)cc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1cc(C)c(Sc2cc(Br)cc(OCC(C)C)c2)cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-5-isobutoxy-benzene (1.66 g; 5.4 mmol), (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester (1.0 g; 4.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.11 g; 0.12 mmol), and 1,1′-bis-(diphenylphosphineo)ferrocene (0.14 g; 0.25 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (2.3 mL) and NMP (10 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140° C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4×100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (10:1→1:1). Yield: 1.3 g; 67%. HPLC-MS: m/z: 467.0 (M+); Rt: 3.10 min
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:18][CH:9]2[C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13]3)=[CH:4][C:3]=1[CH3:19]>C1C=CC=CC=1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]2=[O:18])=[CH:4][C:3]=1[CH3:19]
Reactant: Cc1cc(C23CC(C)(C)CC(C)(C)C2O3)ccc1F
Solvent: c1ccccc1
Solvent: CCOCC
Product: Cc1cc(C2CC(C)(C)CC(C)(C)C2=O)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a cooled solution (0° C.) of the epoxide from Example 1, Step A above (32.7 g, 125 mmol) in benzene (200 ml) is added dropwise 7.6 ml BF3 ·OEt2 (62 mmol). The cooling bath is removed and the reaction mixture warmed to room temperature and stirred for 2 hours. The benzene is removed under reduced pressure and provides a residue which is dissolved in ether (300 ml) and washed with saturated ammonium chloride. The ether layer is concentrated under reduced pressure to provide 26 g (80%) of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohexanone. The ketone is recrystallized from pentane to give a white solid; m.p. 63°-64° C.: 1H NMR δ=1.05 (s,3), 1.1 (s,3), 1.3 (s,3), 1.32 (s,3), 1.75 (s,2), 2.0 (q,2), 2.3 (s,3), 3.95 (dd,1), 6.95 (m,3).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=[CH:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:4][CH:3]=1.I[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cu].ClC1C=CC=CC=1Cl>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([N:1]([C:2]2[CH:23]=[CH:22][C:5]([CH3:6])=[CH:4][CH:3]=2)[C:2]2[CH:23]=[CH:22][C:5]([CH:6]=[C:7]3[C:8]4[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=4[CH:10]=[CH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]3=4)=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=C3c4ccccc4C=Cc4ccccc43)cc2)cc1
Reaction time: 7 h
Yield: 149.9 %

Procedure:
To 30 ml of o-dichlorobenzene, were added 7.90 g (26.7 mmol) of the 5-(4-aminobenzylidene)-5H-dibenzo[a,d]cycloheptene previously obtained, 22.0 g (101 mmol) of p-iodotoluene, 11.0 g (79.6 mmol) of anhydrous sodium carbonate and 2.2 g of copper powder. The mixture was refluxed with stirring for 7 hours in an oil bath kept at around 190° C. After the reaction was completed, the reaction was subjected to suction filtration and the filtrate was successively washed with an aqueous 35% sodium thiosulfate solution and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the resulting residue was added about 60 ml of acetone, and the precipitated crystals were collected by filtration. The crystals obtained were further recrystallized using an ethyl acetate/n-hexane mixed solvent to obtain 9.52 g of 5-[4-(di-p-tolylamino)benzylidene)-5H-dibenzo[a,d]cyclo heptene. Yield: 75.0%; m.p.: 168.0 to 169.0° C.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][C:42]([CH:45]3[CH2:50][CH2:49][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56](O)=[O:57])(=[O:53])=[O:52])[CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][C:42]([CH:45]3[CH2:50][CH2:49][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56]([NH:27][OH:28])=[O:57])(=[O:52])=[O:53])[CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)NO
Yield: 82 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(4-chlorophenyl)pyrimidin-2-yl]piperidine-1-sulfonylmethyl}-3-methylbutyric acid (0.172 g), to give the title compound as a cream solid (0.146 g, 82%).