Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].N[C:11]1N=C(O)C=CC=1.BrBr>C(O)(=O)C.O>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:11])=[CH:5][CH:4]=1
Reactant: Nc1nc(O)ccc1Br
Reactant: Nc1cccc(O)n1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)c(N)n1
Reaction time: 0.25 h

Procedure:
In accordance with scheme 1, the compound of formula V (6-amino-5-bromo-pyridin-2-ol) may be prepared as described in Kelly, T. R.; Jagoe, C. T.; Gu, Z. Tetrahedron Letters 1991, 32, 4263-4266) as follows: To a solution of 6-amino-pyridin-2-ol in acetic acid at room temperature is added bromine and stirred for 15 min. The mixture is diluted with water and the precipitate is filtered off. The filtrate is extracted and the combined organic layers are dried and evaporated to dryness. Then a suspension of 6-amino-5-bromo-pyridin-2-ol is treated with KOH pellets and dimethylsulfate. The mixture is stirred for 4 h at room temperature and evaporated to dryness. The residue is purified and 3-bromo-6-methoxy-pyridin-2-yl-amine (IV) is obtained. Furthermore, a mixture of 3-bromo-6-methoxy-pyridin-2-yl-amine, phenylboronic acid (wherein the phenyl ring may be substituted by R1), Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium II) dichloromethane adduct in dioxane is heated to 110° C. for 2 h. The mixture is concentrated, diluted Na2CO3 aq. is added and extracted. The combined organic phases are dried and evaporated. The residue is purified to yield the corresponding compound of formula II, for example 6-methoxy-3-phenyl-pyridin-2-yl-amine. A mixture 6-methoxy-3-phenyl-pyridin-2-yl-amine (II) and ethoxycarbonyl isothiocyanate is stirred at room temperature for 2 h and afterwards evaporated to dryness. The obtained compound of formula III is then treated with a mixture of hydroxylamine hydrochloride and N-ethyldiisopropylamine (DIPEA). The mixture is heated to 80° C. for 16 h, evaporate to dryness, taken up in water and extracted with diethyl ether. The combined organic phases are dried and evaporated to yield, for example, 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine (Ia). A mixture of 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and a compound of formula R2Cl, for example 3-fluorophenyl carboxylic acid chloride, and NEt3 in dioxane is heated to 90° C. for 16 h. The mixture is purified to give a compound of formula I, for example 3-fluoro-N-(5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-benzamide.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([O:19][C:18]([F:17])([F:27])[F:28])[CH:21]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1C[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of N-Boc-4-methylene-L-proline (1 g, 4.4 mmol) in CH2Cl2 (40 mL) was added 3-(trifluoromethoxy)aniline (0.71 mL, 5.28 mmol), HBTU (1.14 g, 6.6 mmol) and diisopropylethylamine (1.51 mL, 8.8 mmol). The reaction mixture was stirred at RT for 2 days. The mixture was successively washed with 30 mL of a saturated aqueous NaHCO3 solution and an HCl 1M solution. The organic layers were dried (phase separator) and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane/EtOAc:65/35) to give the title compound. TLC, Rf (c-hexane/EtOAc: 1:1)=0.55; MS (LC/MS): 287.0 [M-Boc]+, 385.0 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br.Br[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)[CH:25]=1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: BrCc1cccnc1
Agent: Br
Product: O=C(c1ccc(OCc2cccnc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-(bromomethyl)pyridine hydrobromide. MS (ES+) 366.2
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH3:25])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH3:25])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-methylthiophene-2-carboxamide (67.4 mg) in acetonitrile (10 mL) were added sodium iodide (56.7 mg) and chloro(trimethyl)silane (0.192 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (57.4 mg).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][CH2:17][C@@H:18]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:20]([C:29]3[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=3)[C:19]2=[O:36])=[CH:11][CH:10]=1.[CH2:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:39]#[CH:40]>CN(C=O)C.[Cu]I>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][CH2:17][C@H:18]2[C:19](=[O:36])[N:20]([C:29]3[CH:34]=[CH:33][C:32]([C:40]#[C:39][CH2:38][NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:31][CH:30]=3)[C@@H:21]2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(O)cc2)N1c1ccc(I)cc1
Reactant: C#CCNS(C)(=O)=O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O)cc2)cc1

Procedure:
Triethylamine (7 equivalents) is added to a solution of (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-1-(4-iodophenyl)azetidin-2-one (i-6) (1.00 equivalent), N-prop-2-yn-1-ylmethanesulfonamide (i-5) (1.50 equivalents), tetrakistriphenylphosphine palladium(0) (0.15 equivalents) and copper(I) iodide (0.30 equivalents) in DMF (0.1 M concentration with respect to final product) under a nitrogen atmosphere and the resulting solution aged at room temperature. After completion of reaction, the volatiles are evaporated in vacuo and the crude residue can be purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[CH:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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]>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH2:20]1
Reactant: CC(C)N1CCNCC1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc([N+](=O)[O-])c(OC)cc1N1CCN(C(C)C)CC1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
1-chloro-2,5-bis(methyloxy)-4-nitrobenzene (3.25 g, 15 mmol, TCl America), isopropylpiperizine (3.84 g, 30 mmol, Oakwood Products), cesium carbonate (9.8 g, 30 mmol), Pd2dba3 (1.37 g, 1.5 mmol), and XANTPHOS (1.3 g, 2.25 mmol) were added to degassed dioxane (80 mL) and heated to 100° C. under a water cooled reflux condenser for 12 hours. The dioxane was removed under reduced pressure and the solids were partitioned between methylene chloride (500 mL) and water (500 mL). The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2to give 1-[2,5-bis(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine as a yellow solid (3.5 g, 11.3 mmol, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.09 (d, J=6.60 Hz, 6 H), 2.69-2.73 (m, 4 H), 2.75 (d, J=6.60 Hz, 1 H), 3.23-3.32 (m, 4 H), 3.88 (s, 3 H), 3.94 (s, 3 H), 6.48 (s, 1 H), 7.55 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(N2C(=O)Cc3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
A solution of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydroindol-2-one (1 eq) in dry DMF was treated with NaH (1.1 eq) at RT for 15 mins and then a solution of 2-chloro-N,N-diethyl-acetamide (3.3 eq) and triethylamine (3.3 eq) in three portions and the mixture heated to 60° C. for 6 h. Concentration and purification by prep HPLC gave the title compound.
Reaction SMILES: C(OO)(=[O:3])C.OO.C(OC(=O)C)(=O)C.[Cl:15][CH2:16][CH2:17][N:18]([CH2:44][CH2:45][Cl:46])[C:19]1[CH:20]=[CH:21][C:22]([CH3:43])=[C:23]([CH2:25][C@@H:26]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:24]=1>ClCCl>[C:31]([O:30][C:28](=[O:29])[CH2:27][C@H:26]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:25][C:23]1[CH:24]=[C:19]([N+:18]([O-:3])([CH2:44][CH2:45][Cl:46])[CH2:17][CH2:16][Cl:15])[CH:20]=[CH:21][C:22]=1[CH3:43])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(N(CCCl)CCCl)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CC(=O)OO
Agent: OO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1ccc([N+]([O-])(CCCl)CCCl)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Adapting literature known protocols (Tercel, et al., J. Med. Chem. 1995, 38, 1247-1252; and Kirkpatrick, et al., U.S. Pat. No. 7,399,785), peracetic acid (H3CCO3H) is freshly prepared by adding hydrogen peroxide (H2O2) (1.5 mL of a 35 wt-% aqueous solution, 14.0 mmol) dropwise to acetic anhydride (Ac2O) (1.52 mL, 1.65 g, 16.0 mmol). When the reaction mixture is homogeneous, a solution of tert-butyl(3R)-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]-3-(tert-butoxycarbonylamino)butanoate (6e) (1.61 g, 3.29 mmol) in dichloromethane (DCM) (20 mL) is added with vigorous stirring at about room temperature for about 2 h. The reaction is followed by TLC and/or LC/MS to completion. The reaction is quenched with 2.0 N hydrochloric acid (HCl), and the aqueous layer separated and repeatedly washed with DCM to the organic extracts are colorless. The aqueous phase is evaporated to dryness under reduced pressure, dried over anhydrous sodium sulfate (Na2SO4), and partially reduced in volume. Diethyl ether (Et2O) is added to separate the title compound 3-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]-N,N-bis(2-chloroethyl)-4-methyl-benzeneamine oxide (22a). The material may be purified by silica gel column chromatography.
Reaction SMILES: [F:1][C:2]([F:67])([F:66])[C:3]1[CH:4]=[C:5]([CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:58])[CH2:41][CH2:42][CH2:43][N:44]([CH3:57])[C:45](=[O:56])[CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-])=O)=[CH:49][CH:48]=3)=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7]>C(O)C.[C].[Pd]>[NH2:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C:45]([N:44]([CH2:43][CH2:42][CH2:41][N:40]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]2[C:25]3([CH2:24][CH2:23][N:22]([CH2:21][CH2:20][C@:11]4([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]5[CH:4]=[C:3]([C:2]([F:1])([F:66])[F:67])[CH:61]=[C:60]([C:62]([F:64])([F:63])[F:65])[CH:59]=5)[CH2:12]4)[CH2:27][CH2:26]3)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[CH3:58])[CH3:57])=[O:56])=[CH:48][CH:49]=1
Reactant: CN(CCCN(C)C(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Agent: [Pd]
Solvent: CCO
Product: CN(CCCN(C)C(=O)Cc1ccc(N)cc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
The compound (212 mg, 0.225 mmol) obtained in Example 57a was dissolved in ethanol (10 mL), 10% palladium-carbon (42 mg, 20% by weight) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (194 mg; yield, 98%) as a yellow oily substance.
Reaction SMILES: CO[C@](C1C=CC=CC=1)(C(F)(F)F)C(Cl)=O.[Cl:17][CH2:18][CH:19]([OH:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:17][CH2:18][C@H:19]([OH:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(O)CCl
Agent: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Product: CCOC(=O)C[C@@H](O)CCl

Procedure:
The resulting product was esterified with (R)α-methoxy-α-trifluoromethylphenylacetyl chloride, and the ester was analyzed by HPLC. From the area ratio of the chromatogram, the optical yield of the product was found to be 97.2% ee.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[N:7][C:6]=2[NH:5][C:4]1=[O:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:29]([O:32][CH2:33][CH2:34]Br)(=[O:31])[CH3:30]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:29]([O:32][CH2:33][CH2:34][N:5]1[C:6]2[N:7]=[CH:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]=2[C:11](=[O:12])[N:3]([CH2:1][CH3:2])[C:4]1=[O:22])(=[O:31])[CH3:30]
Reactant: CCn1c(=O)[nH]c2ncn(Cc3ccc(OC)cc3)c2c1=O
Reactant: CC(=O)OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CC#N
Product: CCn1c(=O)c2c(ncn2Cc2ccc(OC)cc2)n(CCOC(C)=O)c1=O
Reaction time: 7 h
Yield: 75 %

Procedure:
Acetonitrile was added to a mixture of Compound 5A (about 1.0 mole), anhydrous potassium carbonate (about 1.5 moles) and tetrabutylammonium hydrogen sulfate (about 0.05 mole). 2-bromoethyl acetate (about 1.5 moles) was added in three separate portions (0.72 mole in the beginning, another 0.45 mole after about 2 hours of reaction, and then the remaining 0.33 mole after about another 1 hour of reaction) during the course of the reaction at about 80–85° C. The total reaction time was about 7 hours. The reaction mixture was cooled to about room temperature and filtered. The filtrate was concentrated. Aqueous isopropanol was added to crystallize the product. The product was filtered, washed with aqueous isopropanol, and dried to provide Compound 6A in about a 75–80% yield.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]4)=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH:22]4[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]4)=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(S(C)(=O)=O)C2)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)N1CCCC(Oc2ccc3c(c2)OCCn2c-3c(C3CCCCC3)c3ccc(C(=O)O)cc32)C1
Temperature: 55 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a solution of methyl 12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a -azadibenzo[a,e]azulene-9-carboxylate (47 mg, 0.085 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (0.5 ml), and the mixture was stirred at 55° C. for 2 hr. The mixture was adjusted to pH 6.5 by adding 1N hydrochloric acid (2 ml), and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. Hexane and ethyl acetate were added to the obtained residue, and the precipitate was collected by filtration, washed with hexane and dried in vacuo to give 12-cyclohexyl-3-(1-methanesulfonylpiperidin-3-yloxy)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (25 mg, yield 56%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@@H:19]([C:24]([O:26]C)=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+].[ClH:35]>C1COCC1.CO>[ClH:35].[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCCC[C@@H](NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(=O)O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
890 mg of methyl N-({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)-D-norleucinate Example 19 (2 mmol, 1 equivalent) were dissolved in 16 ml of THF/methanol (1:1), 10 ml of 1 N aqueous lithium hydroxide solution (10 mmol, 5 equivalents) were added and the mixture was stirred at 45° C. for 2 h. With ice cooling, the mixture was then adjusted to pH 5-6 using 6 N aqueous hydrochloric acid, and the organic solvent was removed under reduced pressure. A little water was added to the residue, and the mixture was extracted repeatedly with dichloromethane/methanol=100:5. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue obtained was dried under high vacuum. This gave 844 mg (95% of theory; purity: 98%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:2].[CH2:15]([C:17]1[CH:22]=[C:21]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([CH2:32][CH3:33])[C:18]=1O)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[CH2:15]([C:17]1[CH:22]=[C:21]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([CH2:32][CH3:33])[C:18]=1[O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:12][CH2:13][CH3:14])[CH3:16]
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(CC)c1O
Reactant: CCOC(COCCCCO)OCC
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(COCCCCOc1c(CC)cc(OC(=O)c2ccccc2)cc1CC)OCC
Yield: 97.9 %

Procedure:
To a mixture of 16.0 g of 4-(2,2-diethoxyethoxy)butanol, 18.9 g of 2,6-diethyl-4-benzoyloxyphenol, 20.2 g of triphenylphosphine and 200 ml of tetrahydrofuran was slowly added dropwise 17.0 g of dilsopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 31.4 g of 3,5-diethyl-1-benzoyloxy-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene (yield, 88%), nD24.8 1.5129.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([CH3:3])[CH3:2].CN(C)[CH:14]=[O:15].P(Cl)(Cl)(Cl)=O>>[CH:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[O:10][CH3:11])[CH:14]=[O:15])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COc1ccccc1C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C=O)cc1C(C)C
Temperature: 80 °C
Yield: 84.5 %

Procedure:
A 5 L three-necked round bottom flask was equipped with mechanical agitation and provided with an inert gas blanket. The flask was charged with 1-isopropyl-2-methoxybenzene (859 g, 5.85 moles) and dimethylformamide (1584 mL, 20.46 moles), and the mixture was heated to 80° C. Phosphorus oxychloride (2690 g, 17.54 moles) was added to the reaction mixture over approximately 3 h while maintaining the temperature of the reaction mixture between 80° C. and 90° C. The addition of POCl3 caused an immediate color change with continuous darkening over the course of the reaction. The reaction mixture was maintained at 80° C. for approximately 16 h, then checked by HPLC for presence of unreacted starting materials. The reaction mixture was quenched by slow addition over approximately 2 h to icewater (8 kg total, 5 kg ice); alternatively the reaction mixture was added over approximately 3 h to deionized water (10 L) in a jacketed 30 L reactor whose cooling bath was maintained between 0° and 5° C. Ethyl acetate (12 L) was added to the quenched reaction with stirring. After settling, the layers were separated, and the aqueous layer was washed with additional ethyl acetate (4 L). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (4 L) and saturated aqueous sodium chloride (4 L). The ethyl acetate was removed by vacuum distillation to yield 3-isopropyl-4-methoxybenzaldehyde (881 g, 86.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1

Procedure:
72.1 Using general method G, 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (prepared according to WO 2003045912) was activated with 4-nitrophenyl chloroformate to give [2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester. White solid.