Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][CH:29]([CH3:32])[CH2:30][OH:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][CH:29]([CH3:32])[CH2:30][OH:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Reactant: CC(N)CO
Product: CCn1c(=O)c(C(=O)NC(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 64.9 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.081 mmol) and 2-amino-1-propanol (0.052 mL, 0.648 mmol) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1-methylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (21 mg, 66% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.34 (d, J=7.2 Hz, 1 H), 8.55 (s, 1 H), 7.36 (s, 1 H), 7.18-7.14 (m, 2 H), 7.05-7.01 (m, 2 H), 4.28 (m, 1 H), 4.21-4.14 (m, 4 H), 3.79 (dd, J=10.8, 3.6 Hz, 1 H), 3.68 (dd, J=10.8, 6 Hz, 1 H), 1.32 (d, J=6.8 Hz, 3 H), 1.24 (t, J=6.8 Hz, 3 H); HRMS m/z calcd for C21H23FN3O4: 400.1667. Found: 400.1674.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)(=O)CC.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[C:7]([C:6](=[O:5])[CH2:7][CH3:8])[CH:8]=1
Reactant: CCC(=O)Oc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1cc(Br)ccc1O
Temperature: 0 °C

Procedure:
4-Bromophenyl propionate (34 g, 0.15 mmol) and aluminum chloride (44 g, 0.3 mmol) were heated together at 100° C. for 30 mins. The solution became dark and hydrogen chloride gas was evolved. After cooling, the reaction mixture was carefully poured into ice water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give the residue, which was purified by column chromatography to give 1-(5-bromo-2-hydroxyphenyl)propan-1-one. (20 g, 59%) 1H NMR (CDCl3, 400 MHz): 1.24 (t, 3H), 2.98-3.04 (m, 2H), 6.88 (d, 1H), 7.52 (t, 1H), 7.76 (s, 1H).
Reaction SMILES: CC#N.[OH2:4].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl>CC#N>[CH2:7]([CH:6]1[CH2:5][O:4]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O
Reactant: C=CCCCCCCCCCC
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCC1CO1
Yield: 99 %

Procedure:
Under a flow of F2 (10% in N2) of 20.0 ml min−1 (3.33 mmol h−1) passed through conduit 12, MeCN:H2O (4:1, 4.95 ml) was added to conduit 16 at a rate of 9.90 ml h−1 (110.0 mmol h−1) and dodec-1-ene 24 (0.18 g, 1.07 mmol) (in a 1:1 mixture of DCM:MeCN) was added to conduit 38 at a rate of 9.90 ml h−1. All reaction fluids were collected in pot 22 containing sodium bicarbonate solution 25 (50 ml). The reaction mixture was then added to another 25 ml of sodium bicarbonate solution, washed with DCM (3×75 ml), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 2-decyloxirane (0.195 g, 1.06 mmol, 99%) as a yellow oil, with no further purification required.
Reaction SMILES: [NH:1]1[C@H:4]([C:5]([NH:7][C@H:8]([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][CH:11]=2)=[O:6])[CH2:3][C:2]1=[O:25].C1C=CC2N(O)N=[N:32][C:30]=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CN>CN(C=O)C.CO>[NH:1]1[C@H:4]([C:5]([NH:7][C@H:8]([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([NH:32][CH3:30])=[O:20])=[O:16])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][CH:11]=2)=[O:6])[CH2:3][C:2]1=[O:25]
Reactant: On1nnc2ccccc21
Reactant: O=C1C[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CC(=O)N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In 2 ml of DMF were dissolved 300 mg of Nα -[(S)-2-azetidinone-4-carbonyl]-L-histidyl-L-proline (13) (obtained in Example 3), 116 mg of HOBT, and 177 mg of DCC and after stirring for 7 hours at room temperature, the solution was cooled in an ice bath. Then 0.6 ml of a methanol solution of 30% methylamine was added to the solution and the mixture was reacted overnight with stirring at 2° to 6° C. Insoluble matters were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue thus formed was purified by column chromatography using LiChroprep Si 60(size B). By using chloroform-methanol-aqueous ammonia (40:10:1) as the eluant, Nα-[(S)- 2-azetidinone-4-carbonyl]-L-histidyl-N-methyl-L-prolinamide (46) was obtained. The product was dissolved in water and then lyophilized. The amount of the product thus obtained was 149 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH:6]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:9])[C:5]([CH3:17])([CH3:16])[CH2:4][O:3]1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:8]([CH:6]1[C:5]([CH3:17])([CH3:16])[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[O:7]1)=[O:9]
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: Nc1ccccc1O
Product: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)Nc2ccccc2O)O1
Yield: 96.8 %

Procedure:
3-[N-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid (0.26 g) and 0.13 g of o-aminophenol were reacted in the same manner as in Reference Example 15 to obtain 0.34 g of the objective compound (yield: 98%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>N1C=CC=CC=1.CCOC(C)=O.[Pd].[Cu-]=O>[OH:18][CH2:13][CH2:14][CH2:15][C:16]1[O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH:17]=1
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: C#CCCCO
Agent: O=[Cu-]
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2oc(CCCO)cc2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
See Fancelli D.; Fagnola, M. C.; Bedeschi, A. Solid phase Synthesis of 2-Substituted Benzofurans via the Palladium-catalyzed Heteroannulation of acetylenes. Tetrahedron Letters 1997, 38, 2311-2314. A mixture of methyl 4-hydroxy-3-iodobenzoate (93) (35 g, 125.9 mmol), 4-pentyn-1-ol (11.00 g, 130.7 mmol) and copper (I) oxide (12.62 g, 88.2 mmol) in dyr pyridine (150 mL) was stirred at 100-120° C. overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc (200 mL), filtered through a Celite pad (5 cm) and concentrated. The residue was dissolved in EtOAc (300 mL), washed with 2 M HCl (50 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. Column chromatography (SiO2, EtOAc/hexanes, 1/1) followed by recrystallization (hexanes/diethyl ether, 2/1) afforded 95 as light yellow crystals (14.39 g, 49%). 1H NMR (DMSO-d6) δ8.20 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.74 (s, 1H), 4.59 (b, 1H), 3.49 (b, 2H), 3.86 (s, 3H), 2.84 (t, J=7.1 Hz, 2H), 1.85 (m, 2H). HPLC (method B) tR 4.20 min (100.00 area %).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)[N:22]=[C:21]4[NH:32][CH:33]=[CH:34][C:20]=34)[CH:18]=2)=[CH:9][CH:8]=1.[OH-].[Na+].O.CC(O)=O>CO>[CH3:31][C:27]1[N:26]=[C:25]([C:23]2[N:22]=[C:21]3[NH:32][CH:33]=[CH:34][C:20]3=[C:19]([C:17]3[CH:18]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([CH2:6][NH:5][CH2:4][C:3]([OH:35])=[O:2])=[CH:8][CH:9]=4)[CH:14]=[N:15][CH:16]=3)[CH:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CNCc1ccc(-c2cncc(-c3cc(-c4cccc(C)n4)nc4[nH]ccc34)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(-c2cc(-c3cncc(-c4ccc(CNCC(=O)O)cc4)c3)c3cc[nH]c3n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-{5-[6-(6-methyl-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyridin-3-yl}-benzylamino)-acetic acid methyl ester (Example 133) (1 eq, 0.216 mmol, 100 mg) in MeOH (10 ml) is added aqueous NaOH solution (1 M, 25 eq, 5.39 mmol, 5.39 ml). The resulting mixture is stirred for 1 h at r.t. Water is added, then the mixture is adjusted to pH 4 using AcOH, then washed with DCM/isopropanol (3:1). The aqueous layer is concentrated in vacuo, and the remaining residue is purified by column chromatography (DCM/MeOH/NH3) and subsequent reversed phase HPLC giving the title compound; [M+H]+=450; 1H-NMR (400 MHz, CD3OD): δ 9.01 (m, 1H), 8.92 (m, 1H), 8.52 (m, 1H), 8.31 (d, 1H), 8.25 (s, 1H), 7.98-7.87 (m, 3H), 7.69-7.62 (m, 3H), 7.40 (d, 1H), 6.73 (d, 1H), 4.32 (s, 2H), 3.70 (s, 2H), 2.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3C(C)=NN=C3C(C)(C)N=2)=[CH:4][CH:3]=1.Cl.[NH2:27][C:28]1([C:32]([O:34]CC)=O)[CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[NH:12][C:32](=[O:34])[C:28]3([CH2:29][CH2:30][CH2:31]3)[N:27]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(N)CCC1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)c1nnc(C)n1-2
Agent: Cl
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CCC1)C(=O)N2

Procedure:
A procedure analogous to that set forth in the synthesis of Compound 214 was followed, with the exception that ethyl 1-aminocyclobutanecarboxylate hydrochloride was used as starting material. LRMS (M+H)+: 345 m/z.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:22][CH:23]=1)=[O:33]
Reactant: CC(C)(C)C(=O)Nc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1ccc(OCCOc2ccc(NC(=O)C(C)(C)C)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and N-(4-hydroxy-phenyl)-2,2-dimethyl-propionamide via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C23H29NO6 [M+H]+: 416.4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=2)=[O:15])[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH3:24][C:10]1([CH3:25])[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=1)=[O:15]
Reactant: COc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C(=O)N2CCNCC2(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 780 mg (2.23 mmol) 4-(6-methoxy-pyridine-2-carbonyl)-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 2.00 mL (25.9 mmol) TFA in 10 mL DCM was stirred at RT for 12 h. The solvent was evaporated and the residue triturated with diethyl ether. The precipitate was filtered off, washed with diethyl ether and dried.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[Cl:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[CH3:14])=[O:12])=[CH:9][C:8]=1[C:30]1[CH:31]=[N:32][C:33]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:35]=1[C:36]#[N:37]>CC#N>[Cl:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]([N:13]([CH3:14])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([CH3:27])([CH3:26])[C:24]([OH:2])=[O:25])=[O:12])=[CH:9][C:8]=1[C:30]1[CH:31]=[N:32][C:33]([C:38]([F:41])([F:39])[F:40])=[CH:34][C:35]=1[C:36]#[N:37]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCC(C)(C)CO
Solvent: CC#N
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCC(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To periodic acid (68 mg, 0.30 mmol) in CH3CN (200 μL) at 0° C., Cr(VI)oxide (0.7 mg, 0.0073 mmol) was added and the mixture was stirred for 15 min at 0° C. A solution of 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-N-methyl-benzamide (29 mg, 0.056 mmol) dissolved in CH3CN (200 μL) was added and the mixture was warmed to rt. After 2 hr at rt, the mixture was filtered, rinsed with CH3CN, concentrated, dissolved in MeOH and purified by prep HPLC yielding 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-2,2-dimethyl-propionic acid 52-1. MS: 532.3 (M+H)+, tR=3.65 min (method 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:26][CH:23]1[CH2:25][CH2:24]1)=[O:9]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a toluene solution (1 M) of 5-chloro-2-methylbenzoic acid (1 eq.) and DMF (1.2 eq.) was added at 0° C. oxalyl chloride (1.2 eq.) dropwise over 1 h. The resulting solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane (1 M), cooled to 0° C. and added sequentially cyclopropylamine (1.5 eq.) and Hunig's base (2 eq.) dropwise. The resulting suspension was stirred at RT for 18 h. The reaction was quenched with 1 N aq. HCl and extracted with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated in vacuo to ˜1/3 in volume. The resulting white suspension was added an equivalent volume of hexanes and the title compound was isolated via vacuum filtration.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.[N:12]1([CH2:21][C:22]2[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=2)[C:25](OCC)=[O:26])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1>>[CH:1]1([NH:7][C:25](=[O:26])[C:24]2[CH:30]=[CH:31][CH:32]=[C:22]([CH2:21][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cccc(Cn2cnc3ccccc32)c1
Agent: C[Al](C)C
Product: O=C(NC1CCCCC1)c1cccc(Cn2cnc3ccccc32)c1

Procedure:
N-Cyclohexyl 3-(1H-benzimidazylmethyl)benzamide was prepared by the method of example 9 starting with cyclohexylamine and reacting with trimethylaluminium and ethyl 3-(1H-benzimidazylmethyl)benzoate.
Reaction SMILES: [CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15].C(#N)C.[Br:22]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>O>[CH3:1][CH:2]([CH2:17][CH3:18])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([Br:22])[CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(C)COc1ccccc1OCC(C)CC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCC(C)COc1ccc(Br)cc1OCC(C)CC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1,2-Bis(2-methylbutyloxy)benzene (338 g, 1.35 mol) together with 2.5 l of acetonitrile was placed in a reaction vessel, cooled to 0° C. and admixed with 264 g (1.48 mol) of N-bromosuccinimide. The mixture was warmed to RT and stirred for another 90 minutes. After taking off the acetonitrile, the residue was admixed with toluene and water and the phases were separated. After shaking the aqueous phase with toluene and drying the organic phase over Na2SO4, the toluene was taken off. The crude product was purified by double fractional distillation under reduced pressure. This gave the product as a colorless oil (145° C., 1.3 mbar): 275 g (62%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH2:14][OH:15])([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl>[C:1]([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH2:14][O:15][S:33]([CH3:32])(=[O:35])=[O:34])([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CO)O2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COS(C)(=O)=O)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
In 50 ml of dichloromethane was dissolved 0.5 g of 5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 47 and combined with 0.18 g of triethylamine and 0.2 g of methanesulfonyl chloride, and the mixture was stirred at room temperature for 24 hours. Then, the reaction mixture was combined with water and extracted with ethyl acetate, and the organic layer was washed with 10% hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 33% ethyl acetate to give 0.55 g of 5-acetoxy-4,6-di-t-butyl-2-methanesulfonyloxymethyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 89%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([NH:14][C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])=[O:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([NH:14][C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])=[O:16])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-c2ccc(O)cc2)nsc1NC(=O)[C@@H]1C[C@H]1C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1
Temperature: 45 °C
Yield: 33.4 %

Procedure:
To a dry flask containing (R,R)—N-[3-(4-hydroxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide (100 mg, 0.347 mmol) is added dry acetone (2 mL), K2CO3 (50 mg, 0.347 mmol), and methyl iodide (19 μL, 0.313 mmol). The reaction mixture is heated 16 h at 45° C. and treated with additional methyl iodide (19 μL, 0.313 mmol). After heating for another 6 h, the solvent is evaporated, and the residue is partitioned between ethyl acetate and water. The ethyl acetate solution is washed (satd aqueous K2CO3 (twice) and brine), dried (MgSO4), and the solvent evaporated. Chromatography over silica gel, eluting with EtOAc/hexanes, affords (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropane-carboxamide (35 mg, 33%) as a white solid. 1H NMR; ES-MS: m/e 303 (m+1).
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=2)=[CH:12][N:13]=1)=O)(C)(C)C.[C:24](N1CCNCC1)(=O)C.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:24][O:23][C:21](=[O:22])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([S:14][C:11]2[S:10][C:9]([NH2:8])=[N:13][CH:12]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Sc2cccc(C(=O)O)c2)s1
Reactant: CC(=O)N1CCNCC1
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Temperature: 55 °C
Yield: 100.1 %

Procedure:
A suspension of 2-tert-butoxycarbonylamino-5-[(3-carboxyphenyl)thio]thiazole (528 mg, 1.5 mmol), N-acetylpiperazine (239 mg, 1.87 mmol), ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (400 mg, 2 mmol), 1-hydroxy-7-azabenzotriazole (272 mg, 2 mmol) and diisopropylethylamine (560 μL, 4 mmol) in THF (20 mL) was heated to 55° C. for 2 h. The mixture was cooled to rt. and concentrated. The residue was purified using column chromatography on silica gel eluted with 2% methanol in dichloromethane followed by 5% methanol in dichloromethane to obtain the titled compound (400 mg, 58%) as a white foam. E. 4-Acetyl-1-[3-[(2-aminothiazol-5-yl)thio]benzoyl]piperazine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH:13]2[C:28](O)=[O:29])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[C:32]([O:36][NH2:37])([CH3:35])([CH3:34])[CH3:33].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:32]([O:36][NH:37][C:28]([CH:13]1[CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:16][CH2:17][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:29])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2C(=O)O)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2C(=O)NOC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of (+)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxylic acid (100 mg, 0.23 mmol) in methylene chloride (5 ml) is added O-t-butylhydroxylamine hydrochloride (35 mg, 0.28 mmol), dimethylaminopyridine (37 mg, 0.30 mmol), and dicyclohexycarbodiimide (57 mg, 0.28 mmol). After stirring overnight, the reaction is diluted with hexanes and the precipitated solid filtered off. The solution is concentrated and the crude product is purified by silica gel chromatography (elution with 2:1 ethyl acetate-hexanes with 1% acetic acid) to provide (+)-N-(t-butyloxy)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxamide.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:2][CH2:3][OH:4])=[N:7][CH:8]=1
Reactant: OCCBr
Reactant: Cc1ccc(O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCCO)nc1

Procedure:
A suspension of 0.291 ml (4.12 mmol) of 2-bromoethanol, of 0.3 g (2.75 mmol) of 2-hydroxy-5-methylpyridine and of 0.85 g (6.18 mmol) of potassium carbonate in 3 ml of dimethylformamide is vigorously stirred for 12 hours at reflux. The mixture is subsequently diluted with 100 ml of water and extracted with 100 ml of dichloromethane. The organic phase is washed with 50 ml of water, dried over sodium sulphate, concentrated under reduced pressure and then chromatographed on a silica column, elution being carried out with a mixture of hexane and ethyl acetate. The expected product is thus isolated.