Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12]([C:28]#[C:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[CH3:27][N:25]([CH3:26])[C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:18]=[C:13]3[C:12]([C:28]#[C:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(C#Cc2ccccc2)cn3S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(-c2cnc3[nH]cc(C#Cc4ccccc4)c3c2)cc1
Temperature: 90 °C
Yield: 28.1 %

Procedure:
To sulfonamide 21 (36.9 mg, 0.077 mmol) in EtOH (770 μL) was added 10% aq. NaOH (386 μL) and the reaction mixture heated at 90° C. for 1 h. It was then poured onto water (5 mL), extracted with ethyl acetate (4×10 mL) and the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by preparative LCMS (column LUNA 10μ C18(2) 00G4253-V0 250×50 mm) using water-acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give inhibitor 22 as a white solid (7.3 mg, 28%); 1H NMR (400 MHz, CDCl3) δ 6.86 (d, J=8.85 Hz, 2H), 7.31-7.39 (m, 3H), 7.57-7.62 (m, 5H), 8.24 (d, J=1.87 Hz, 1H), 8.59 (d, J=1.80 Hz, 1H), 9.83 (bs, 1H).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[CH:19][C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)=[CH:23][CH:22]=2)[CH2:25][CH2:26]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Product: CN1CCN(c2ccc(-n3c4c(c5ccccc53)CN3CCC4CC3)cc2)CC1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 1-(4-bromophenyl)-4-methylpiperazine (255 mg, 1.0 mmol; Accela Chembio) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.92-2.11 (m, 4H) 2.37 (s, 3H) 2.61-2.71 (m, 4H) 2.86-2.92 (m, 1H) 3.03-3.28 (m, 8H) 4.31 (s, 2H) 6.95-7.06 (m, 3H) 7.10-7.21 (m, 4H) 7.32-7.40 (m, 1H); MS (DCI/NH3) m/z 387 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH:8](O)[C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]1=2.FC(F)(F)C(O)=O.C(OCC)(=O)C>O>[CH2:1]([O:4][C:5]([N:7]([C:16]1[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13][CH:17]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC(O)C(=O)O
Reactant: c1ccc2sccc2c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N(CC(=O)O)c1csc2ccccc12
Yield: 88 %

Procedure:
A solution of 5.15 g. (29.4 mM) of DL N-allyloxycarbonyl-α-hydroxyglycine and 3.95 g. (29.4 mM) of benzo[b]thiophene in 40 ml. of trifluoroacetic acid was stirred at 22.5° C. for eighteen hours. The reaction mixture was then concentrated by evaporation under reduced pressure to give an oil, and the oil was dissolved in a mixture of 100 ml. of ethyl acetate and 100 ml. of water. The organic layer was separated, and the aqueous layer was extracted twice more with 50 ml. portions of fresh ethyl acetate. The organic extracts were combined, washed with water, and then extracted twice with 100 ml. portions of 10% aqueous sodium bicarbonate. The aqueous extracts were combined, added to 100 ml. of fresh ethyl acetate, and acidified to pH 2.0 by the addition of conc. hydrochloric acid. The organic layer was separated and the aqueous acid layer was extracted with two 50 ml. portions of fresh ethyl acetate. The organic portions were combined, dried, and the solvent was removed by evaporation to provide 7.55 g. (88% yield) of N-allyloxycarbonyl-(3-benzothienyl)glycine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[N:4][CH:3]=1.[CH2:13]([Li])CCC.IC.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: Clc1cncc(NCC2CC2)n1
Reactant: [Li]CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CC1CC1)c1cncc(Cl)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 6-chloro-N-(cyclopropylmethyl)pyrazin-2-amine (0.60 g) in tetrahydrofuran (5 mL) was added dropwise n-butyllithium (3.06 mL, 1.6 M hexane solution) at −78° C. The mixture was stirred at −78° C. for 5 min, and iodomethane (1.02 mL) was added dropwise thereto. The mixture was stirred at −78° C. for 30 min, and further stirred at 0° C. for 1 hr. Saturated aqueous sodium thiosulfate solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5-*15% ethyl acetate/hexane) to give the title compound (0.46 g, 70%) as a pale-yellow oil.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[F:5][C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][CH:9]=[C:10]2[C:14]=1[C:13](=[O:15])[CH2:12][CH2:11]2.CO>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[F:5][C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:8][CH:9]=[C:10]2[C:14]=1[C:13](=[O:15])[NH:1][CH2:12][CH2:11]2
Reactant: O=C1CCc2ccc(C(F)(F)F)c(F)c21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C1NCCc2ccc(C(F)(F)F)c(F)c21
Yield: 56.1 %

Procedure:
Sodium azide (492 mg, 7.5688 mmol) was added portion wise to a stirred solution of 7-fluoro-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (I-77c: 500 mg, 2.2935 mmol) in TFA (15 mL) over a period of 5 hours at 80° C. The reaction was monitored by TLC (5% methanol in CHCl3). The reaction mixture was concentrated under reduced pressure, followed by the addition of ice. The precipitated solid was filtered, washed with water (20 mL) and dried under reduced pressure to yield the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 300 mg of the product (56.1% yield).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([OH:19])([CH3:18])[CH3:17].[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[C:27](O)[CH:26]=[N:25][CH:24]=1.C1C=CC=CC=1>C(Cl)(Cl)Cl.Cl[Cu]>[CH:16]([O:19][C:27]1[CH:26]=[N:25][CH:24]=[C:23]([CH:28]=1)[C:22]([O:21][CH3:20])=[O:30])([CH3:18])[CH3:17]
Reactant: COC(=O)c1cncc(O)c1
Reactant: CC(C)O
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)c1cncc(OC(C)C)c1
Temperature: 105 °C
Reaction time: 13 h
Yield: 46.8 %

Procedure:
A solution of 677 mg (3.28 mmol) of dicyclohexylcarbodiimide (DCC), 0.3 mL (3.92 mmol) of isopropanol, and 7.7 mg (0.078 mmol) of CuCl was heated at 60° C. After 13 h, 460 mg (3.0 mmol) of 5-hydroxynicotinic acid methyl ester and 10 mL of benzene were added and heated at 105° C. for 24.5 h. The mixture was diluted with chloroform and filtered. The organic layer was washed with 15 mL of sat. NaHCO3, water, and brine and dried over Na2SO4. Purification by flash silica gel chromatography (100% CHCl3) provided 274 mg of methyl 5-isopropoxynicotinate as a yellow oil in 47% yield.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[C:7](C)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N)(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)C(C)C>>[C:1]([NH:5][C:6](=[O:11])[CH:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)N
Product: CC(C)C(=O)NC(C)(C)C
Yield: 96 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of tert-butylamine (11.3 mL, 105 mmol) and triethylamine (14.9 mL, 105 mmol) with isobutyryl chloride (10.8 mL, 100 mmol) afforded LiPr,tBuH as white crystalline solid (13.75 g, 96%) upon sublimation at 55° C./0.05 Torr: mp 117-119° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(C)C=O>[Pd].C(OCC)(=O)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>[CH:12]([C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)=[CH2:13]
Reactant: COC(=O)c1cccnc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ncccc1C(=O)OC
Temperature: 55 °C
Reaction time: 7 h

Procedure:
2-Ethenyl-3-pyridinecarboxylic acid, methyl ester (12) is prepared as follows: a mixture of 19.7 g (115 mmol) of 2-chloro-3-pyridinecarboxylic acid, methyl ester (11), 38.3 g (120.8 mmol) of vinyltributyltin, 1.48 g (2.1 mmol) of bis(triphenylphosphine)palladium (II) chloride 100 mg of 2,6-ditertbutyl-4-methylphenol, and 250 mL of N,N-dimethylformamide is stirred at 55° C. for 7 hours, then treated with 1.63 g 15.1 mmol) of additional vinyltributyltin and 1 g of palladium catalyst. The mixture is heated further at 40° C. for 61 hours, then concentrated at 60° C./5 mm to leave a greenish oil that is dissolved in ethyl acetate and filtered through a pad of silica gel (230-400 mesh). The filtrate is diluted with additional ethyl acetate and the organic phase is washed with water, dried, and concentrated to an oil. The oil is distilled, with material collected in the 80°-95° C./0.14 mm ranger to leave 24.5 g of an oil that is ca. 75% product by GC. The oil is dissolved in dichloromethane:hexanes (1:1) and loaded onto an 8 x 15 cm of silica gel column (230-400 mesh). The column is eluted with the same solvent as above with 500 mL fractions collected. Product fractions are combined and carefully distilled at 65°-67° C./0.15 mm to leave 13.6 g of clear oil, >95% pure by GC, that is sufficiently pure to use directly in the next step.
Reaction SMILES: [BrH:1].[NH+]1C=CC=CC=1.[CH3:8][O:9][N:10]=[C:11]([C:17]([O:21][CH3:22])([O:19][CH3:20])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].O>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[N:10][O:9][CH3:8])[C:17]([O:21][CH3:22])([O:19][CH3:20])[CH2:18][Br:1])[CH3:16]
Reactant: CCOC(=O)C(=NOC)C(C)(OC)OC
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=NOC)C(CBr)(OC)OC

Procedure:
Pyridinium hydrobromide perbromide (1.82 g) was added to a solution of ethyl 2-methoxyimino-3,3-dimethoxybutyrate (syn isomer, 1.0 g) in dry tetrahydrofuran (10 ml) and heated under reflux for an hour. The resultant solution was poured into water (30 ml) and extracted with diethyl ether (10 ml×2). The extract was washed with 5% aqueous sodium thiosulfate solution (5 ml×5) and a saturated aqueous solution of sodium chloride (10 ml×1) successively. The solution was dried over magnesium sulfate and evaporated under reduced pressure to give ethyl-2-methoxyimino-3,3-dimethoxy-4-bromobutyrate (syn isomer, 2.02 g).
Reaction SMILES: [CH3:1][NH2:2].CO.[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:12]([CH:17]=O)[C:13]=1[C:14]([NH2:16])=[O:15])=[O:7].[BH4-].[Na+]>O1CCCC1.CC(C)=O>[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:12]([CH2:17][NH:2][CH3:1])[C:13]=1[C:14]([NH2:16])=[O:15])=[O:7]
Reactant: CN
Reactant: NC(=O)Nc1[nH]c(-c2cccc(Cl)c2)c(C=O)c1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CNCc1c(-c2cccc(Cl)c2)[nH]c(NC(N)=O)c1C(N)=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
40% Methylamine in methanol (1 mL, 9.8 mmol) was added to a suspension of 2-aminocarbonylamino-5-(3-chlorophenyl)-4-formylpyrrole-3-carboxamide (Compound No. 17-1, 45 mg, 0.15 mmol) in tetrahydrofuran (1 mL), and the mixture was sealed and stirred at 40° C. for 3 hours. Moreover, sodium borohydride (25 mg, 0.66 mmol) was added thereto and the whole was stirred at room temperature for 3 hours. Acetone (5 mL) was added to the reaction solution and concentrated in vacuo. Water (10 mL) was added to the obtained residue, and the precipitated solid was filtered off. The solid was washed with water (10 mL) and the mixed solvent (5.5 mL), which consists of chloroform and ethanol (10:1), dried under reduced pressure to give the target compound (17 mg) as an orange solid (Yield 36%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Cl[C:12]1[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[C:15]([C:23]([F:26])([F:25])[F:24])=[CH:14][N:13]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:12]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[C:15]([C:23]([F:24])([F:26])[F:25])=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: COCCNc1cc(Cl)ncc1C(F)(F)F
Product: COCCNc1cc(NCc2ccc(OC)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Reaction time: 18 h

Procedure:
4-Methoxybenzylamine (485 mg, 3.53 mmol) was added to 2-chloro-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridin-4-amine (intermediate 86, 300 mg, 1.18 mmol) and heated in a MW in a septum sealed vial at 60° C. for 3 h. Conventional heating was then continued for 18 h at 80° C., the reaction mixture cooled, additional 4-methoxybenzylamine (162 mg, 1.18 mmol) added and heating continued at 100° C. for 22 h. The reaction mixture was then heated for 9 h at 120° C., cooled, partitioned between saturated aqueous NaHCO3 solution and DCM, extracted 3X with DCM, the organic layers dried over Na2SO4 and evaporated. The residue was applied to a 24 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 20% EtOAc in DCM. Product containing fractions were combined and evaporated to give the title compound as a white solid. (UPLC-MS 6) tR 0.77; ESI-MS 356.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[CH:7]=1)=[O:4].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>ClCCl>[CH3:11][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)[O:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(NC(=O)CBr)on1
Solvent: ClCCl
Product: Cc1cc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a stirred solution of 2-bromo-N-(3-methylisoxazol-5-yl)acetamide (0.122 g, 0.58 mmol) in anhydrous dichoromethane (4.5 ml) under argon was added 1-BOC-piperazine (0.241 g, 1.30 mmol). The reaction mixture was stirred at room temperature for 2 h under argon, then partitioned between ethyl acetate (100 ml) and 6% aqueous Na2CO3 (50 ml). The organic layer was washed with more 6% aqueous Na2CO3 (50 ml), and concentrated in vacuo. The residue was absorbed on silica gel and the free-running powder was placed on a 10 g isolute column. Elution of the column with 30% ethyl acetate in dichloromethane afforded the title compound as a white solid (0.096 g, 51%). 1H-NMR (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.18 (s, 3H, CH3), 2.45 (t, J=5.1 Hz, 4H, piperazine N(CH2)2), 3.23 (s, 2H, NCH2CO), 3.34 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 6.13 (s, 1H, isoxazole C—H), 11.28 (s, 1H, CONH);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Cl.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([NH:30][C:29]3[CH:31]=[CH:32][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:27][CH:28]=3)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of 4.8 mmol of 2-(4-((5-chloro-3-fluoro-2-pyridinyl)oxy)phenoxy)propanoyl chloride (previously prepared from the corresponding acid) in 15 ml of methylene chloride was added, under N2, to an ice-cooled mixture of 1.03 g (4.8 mmol) of 4-(trifluoromethoxy)aniline hydrochloride, 0.95 g (12 mmol) of pyridine and 25 ml of methylene chloride. The resulting mixture was stirred at ambient temperature overnight and then poured into dilute aqueous HCl. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate, treated with charcoal and MgSO4 and filtered. The filtrates were evaporated to dryness and the residue recrystallized from methylcyclohexane to give 0.34 g of the above-named product as colorless crystals, m.p. 92°-93.5° C. (Compound 37)
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>>[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]2)=[CH:36][CH:35]=1
Reactant: CSc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3cccs3)cc2)C(O)C1
Product: CSc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3cccs3)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 4-methylthio-benzyl chloride [J.Org.Chem. (1988), 53(3),561-569] there was obtained tert-butyl (3RS,4RS)-3-(4-methylsulphanyl-benzyloxy)-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a yellowish oil; MS: 584 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.O=[C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:12]2[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CCCC(=O)c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Product: O=C(O)CCc1c(-c2ccccc2)[nH]c2ccc(Cl)cc12
Yield: 11 %

Procedure:
The expected acid is obtained in the form of a white solid with a yield of 11% by following a procedure analogous to Example 1 and starting from 4-chlorophenylhydrazine and ethyl δ-oxobenzenepentanoate.
Reaction SMILES: [CH3:1][C:2]1([CH2:10][CH2:11][CH3:12])[CH2:8][C:7](=[O:9])[NH:6][C:4](=[O:5])[CH2:3]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][N:6]1[C:7](=[O:9])[CH2:8][C:2]([CH3:1])([CH2:10][CH2:11][CH3:12])[CH2:3][C:4]1=[O:5]
Reactant: CCCC1(C)CC(=O)NC(=O)C1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC1(C)CC(=O)N(CCCCBr)C(=O)C1
Reaction time: 16 h
Yield: 93.1 %

Procedure:
A mixture of the IIa product prepared in Example 1 (25 g; 0.15 mole), 1,4-dibromobutane (33.5 g; 0.15 mole), and K2CO3 (40.6 g; 0.29 mole) was stirred for a period of 16 hrs in 250 mL refluxing acetonitrile. The inorganic solid was removed by filtration and the filtrate was concentrated to a oil which was distilled to give 42.5 g (95%) of a light yellow oil, b.p. 165°-190° at 0.09 mm.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20](C(C5C=CC=CC=5)=C)[C:19]4=[O:35])[CH2:12][CH2:11]3)[C:4]=2[CH:3]=[CH:2]1.Cl>O>[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[NH:20][C:19]4=[O:35])[CH2:14][CH2:15]3)[C:4]=2[CH:3]=[CH:2]1
Reactant: C=C(c1ccccc1)n1c(=O)n(CCN2CCN(c3nccc4occc34)CC2)c2ccccc21
Agent: Cl
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCN1CCN(c2nccc3occc23)CC1
Temperature: 65 °C

Procedure:
A mixture formed from 1.7 g of the product obtained in Step A of this Example, 5 ml of concentrated hydrochloric acid and 20 ml of water is heated at 65° C. for 30 minutes. After cooling, the reaction mixture is washed with ether, rendered basic to pH 9-10 by the addition of potassium carbonate and then extracted with ether. The expected product is obtained by drying and purification by chromatography on silica gel.
Reaction SMILES: [Cl:1]C1C=CC2NC(=O)OC=2C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19](=O)[NH:18][C:17]=2[CH:22]=1>>[Cl:1][C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:22][C:17]=2[N:18]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Product: Clc1ccc2oc(Cl)nc2c1

Procedure:
If the process is carried out as in Example 1, but, instead of 6-chlorobenzoxazolin-2-one, the same amount of 5-chlorobenzoxazolin-2-one is used, then about 130 g, corresponding to 69% of theory, of 2,5-dichlorobenzoxazole, melting point 46°-48° C., are obtained.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:22]([CH:24]([CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1)[C:25](OC)=O)=[O:23].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:20][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:25]=[C:24]([CH2:29][C:30]4[CH:35]=[N:34][CH:33]=[N:32][CH:31]=4)[C:22](=[O:23])[N:21]=3)=[CH:11][CH:10]=2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: COC(=O)C(C=O)Cc1cncnc1
Reactant: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(CCOc3nc(=O)c(Cc4cncnc4)c[nH]3)cc2)cc1Cl
Yield: 6.8 %

Procedure:
Prepared in a manner similar to that described for E149 using 2-{4-[(3-chloro-4-methylphenyl)oxy]phenyl}ethyl imidocarbamate (150 mg, 0.359 mmol) and methyl 2-formyl-3-(5-pyrimidinyl)propanoate (84 mg, 0.431 mmol) and K2CO3 (198 mg, 1.436 mmol) in NMP (2 ml), to afford the title compound (11 mg, 6.83% yield). LCMS: rt=3.33 min, [M+H+]=449
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].B1C2CCCC1CCC2.[OH-:27].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:27])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2ccc(C)c(F)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(CCO)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To the solution of 4-ethenylphenyl 3-fluoro-4-methylphenyl ether (900 mg, 3.94 mmol) in dry THF (30 mL), was added 9-BBN (9.46 mL, 4.73 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (1.2 mL), followed by aq. NaOH (5.26 mL, 15.77 mmol), and 30% H2O2 (4.03 mL, 39.4 mmol). The reaction mixture was heated at 50° C. for 2 h. Then THF was removed under reduced pressure, and the residue was diluted with DCM. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.02 g, 4.14 mmol, 105% yield) as a yellow oil. LCMS: rt=3.29 min, [M+H]=229