Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CO[C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]5=[O:35])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])C=CC=CC=1.C(N(CC)CC)C.[CH2:43]([O:50][CH2:51]C(Cl)=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CO.C(Cl)Cl.[Pd]>[C:44]1([CH2:43][O:50][CH2:51][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]5=[O:35])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)OCC2CN(C(=O)OCc4ccccc4)CCN32)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)OCC2CN(C(=O)COCc4ccccc4)CCN32)C(=O)O1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a flask containing 8-[5-(S)-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-1,2,4a, 5-tetrahydropyrazino[2,1-c][1,4]benzoxazine-3(4H)-carboxylic acid phenylmethyl ester (EXAMPLE 1, 150 mg, 0.31 mmol) in methanol (5 mL) and methylene chloride (5 mL) is introduced 10% palladium on carbon (70 mg). The mixture is placed under a hydrogen balloon for 17 hours, filtered through celite, and concentrated in vacuo. The residue is dissolved in methylene chloride (10 mL) and triethylamine (0.09 mL, 0.62 mmol) and benzyloxyacetyl chloride (0.06 mL, 0.40 mmol) are added at 0° C. under an inert atmosphere. The reaction is warmed to ambient temperature, stirred for 15 hours, washed with water (10 mL) and saline, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (96/4). The appropriate fractions are combined (Rf= 0.46, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.36-7.29, 6.96-6.94, 6.85, 6.70, 4.69, 4.60, 4.50, 4.23-4.15, 3.97-3.91, 3.70-3.52, 3.27, 2.99, 2.82, 2.65, 2.44, 1.98.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=2)[NH:17][CH:16]=[C:15]3[CH:24]2[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:35](Cl)(=O)[CH3:36]>>[CH:2]1([C:1]([NH:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=3)[NH:17][CH:16]=[C:15]4[CH:24]3[CH2:25][CH2:26][N:27]([S:30]([CH2:33][CH3:34])(=[O:31])=[O:32])[CH2:28][CH2:29]3)=[CH:10][CH:11]=2)=[O:3])[CH2:36][CH2:35]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(C)=O)cc4)cc23)CC1
Reactant: CC(=O)Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)C5CC5)cc4)cc23)CC1
Yield: 28 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting cyclopropanecarbonyl chloride (14 μL, 1.37 mmol) for acetyl chloride. Compound was purified by Gilson Preparatory HPLC to afford 19.1 mg of the title compound (28%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Cl:15][C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[C:23]2[C:18](=[C:19]([CH3:35])[CH:20]=[C:21]([CH:33]=[O:34])[CH:22]=2)[N:17]=1>C(Cl)Cl>[Cl:15][C:16]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[C:23]2[C:18](=[C:19]([CH3:35])[CH:20]=[C:21]([CH:33]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=3)[OH:34])[CH:22]=2)[N:17]=1
Reactant: Cc1cc(C=O)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Reactant: Cn1cncc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Product: Cc1cc(C(O)c2cncn2C)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-1-methyl-1H-imidazole (342 mg, 2.12 mmol) in DCM (2.2 mL) was stirred on an ice bath while iPrMgCl—LiCl (1.77 mL, 1.2 M in THF, 2.1 mmol) was added dropwise over 1-2 min under argon. After 10 min stirring at room temperature, the homogeneous amber reaction was added dropwise over 1-2 min to a slurry of 2,4-dichloro-8-methyl-3-phenylquinoline-6-carbaldehyde (460 mg, 1.46 mmol, Intermediate 47, step b) in LaCl3-2LiCl (7.60 mL, 0.56 M in THF, 1.46 mmol) on an ice bath. The reaction was removed from the ice bath immediately following Grignard addition and stirred for 45 min at ambient temperature, and was then partitioned with 9:1 DCM/MeOH (14 mL) and 5 M NH4Cl (0.72 mL). This was filtered over Celite®, and the filter cake washed with 9:1 DCM/MeOH (1×5 mL). The combined clear dark yellow filtrates were dried (Na2SO4), filtered, and concentrated to provide a beige foam. This was concentrated from DCM (3×15 mL) in prelude to MnO2 oxidation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:53]12[CH2:60][CH2:59][CH:56]([CH2:57][CH2:58]1)[C@@H:55](O)[CH2:54]2>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([O:19][C@@H:55]2[CH:56]3[CH2:59][CH2:60][N:53]([CH2:58][CH2:57]3)[CH2:54]2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixture of (S)-3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonyl-amino)propanoic acid (500 mg, 1.35 mmol), DCC (333 mg, 1.61 mmol) and HOBT (247 mg, 1.61 mmol) in dry THF (10 ml) was stirred at RT under nitrogen atmosphere for 1 hour. (R)-quinuclidin-3-ol (205 mg, 1.61 mmol) was added, and the reaction was stirred for 16 hours. The solvent was evaporated, and the residue was portioned between saturated NaHCO3 and EtOAc. The organic phase was washed with brine, dried over Na2SO4 filtered and evaporated to dryness. The residue was triturated with Et2O (30 ml), and the insoluble material was removed by filtration. The solution was evaporated to obtain (S)—((R)-quinuclidin-3-yl) 3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonylamino)-propanoate (590 mg, 91% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[NH:50][C:49]([C@@H:51]3[CH2:55][C@H:54]([CH3:56])[CH2:53][NH:52]3)=[N:48][CH:47]=2)=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:52]1[CH2:53][C@@H:54]([CH3:56])[CH2:55][C@H:51]1[C:49]1[NH:50][C:46]([C:43]2[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=2)=[CH:47][N:48]=1)=[O:8])[CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@@H]1CN[C@H](c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (103 mg, 0.59 mmol, Preparation 2) and HATU (270 mg, 0.71 mmol) were stirred in DMA (2 mL) for 10 min and then 5-(4-bromo-phenyl)-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazole 2 HCl (224 mg, 0.59 mmol, Preparation 8) and N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) were added. The resulting mixture was stirred at RT overnight, diluted with ethyl acetate (50 mL), and washed with water (2×5 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes)). Fractions with desired product were combined and concentrated to give the title compound (183 mg, 66% yield) (m/z): [M+H]+ calcd for C21H27BrN4O3 463.13, 465.12 found 465.3.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[CH2:13]([N+:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>O>[OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[CH2:13]([N+:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]
Reactant: O=C(O)c1cccc(O)c1O
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cccc(O)c1O

Procedure:
To 20 g of water and 3.08 g of 2,3-dihydroxybenzoic acid (20 mmole) at 20° C. was added a 35 weight % solution of tetraethylammonium hydroxide to adjust the pH to 7.9 (8.1 g required, ˜20 mmole). The resulting solution was freeze dried to yield a tan colored free-flowing powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:13][C:12]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14]2)[O:11][N:10]=1.OS(O)(=O)=O.[CH2:28](O)[CH3:29]>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]([O:14][CH2:28][CH3:29])=[O:22])[O:11][N:10]=1
Reactant: O=C1OC2(CC(c3ccc(Cl)cc3Cl)=NO2)c2ccccc21
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CCOC(=O)c1ccccc1-c1cc(-c2ccc(Cl)cc2Cl)no1
Temperature: 0 °C

Procedure:
A solution of 4 g. (0.011 mole) of 3'-(2,4-dichlorophenyl)-spiro[isobenzofuran-1(3H),5'(4'H)-isoxazol]-3-one, 2 ml. of concentrated H2SO4 and 200 ml. of ethanol was held at reflux for 19 hours, cooled, and poured into ice water. The resultant mixture was extracted twice with ether. The ethereal solution was washed twice with water, dried over CaSO4 and concentrated under vacuum to give an oil. The oil was dissolved in hot hexane to afford 4.2 g. of a crystalline solid (96.9%). Recrystallization of the solid from hexane gave 3.1 g. of pure product; m.p. 85°-86° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:28][CH2:29][CH2:30][OH:31]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:28][CH2:29][CH2:30][OH:31])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCS
Reactant: O=C(CCCCCBr)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CCCCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 94 %

Procedure:
Following a procedure similar to that described in Example 67(b), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-6-bromohexanamide [prepared as described in step (a) above] and 2-mercaptoethanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 94% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH:26]=[CH:25]1>C(O)C.[OH-].[Na+]>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28])([OH:23])=[O:22]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
In a mixture of 85 ml of ethanol and 40 ml of 1N aqueous sodium hydroxide solution, 20-aminoeicosanoic acid (500 mg, 1.53 mmoles) was dissolved at 40° C. To the obtained solution, while maintained at 40° C., was gradually added maleic anhydride (3.75 g, 38.3 mmoles) over a period of 3 hours. The pH of the reaction mixture was kept at 8-10 during the addition. The reaction mixture was stirred for 30 minutes and then treated in the same manner as in Reference Example 4, to give N-(19-carboxynonadecyl)maleamic acid (538 mg, 83%) having the following properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.OC1C=C(C(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1cccc(F)c1)c1cccc(O)c1
Agent: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Product: O=C1CC(c2cccc(F)c2)c2ccc(O)cc21
Reaction time: 16 h
Yield: 86 %

Procedure:
The procedure of Step 2 of Example 1 was repeated except for using (E)-3-(3-fluorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one obtained in Step 1 as a starting material instead of (E)-1-(3-hydroxyphenyl)-3-phenylprop-2-en-1-one and being stirred for 16 h to obtain the title compound (86%).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)[CH2:32][CH2:31]1>C1COCC1>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:19]([C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]=[CH:10][CH:11]=[CH:12]4)=[O:21])[CH2:35][CH2:34]2)=[CH:39]1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccc2ncccc2c1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of isobutylchloroformate (0.65g, 5.01 mmol) in dry THF (10 cm3) was added dropwise to a suspension of quinoline-6-carboxylic acid (0.87g, 5.03 mmol) and triethylamine (0.6g, 5.94 mmol) in dry THF (10 cm3) with stirring and cooling at -20° C. Stirring was continued while the temperature rose to ambient over 2 hours, then the mixture was cooled to -20° C. again and a solution of 3-[2-(4-amino-1-piperidyl)ethyl]indole (1.20 g, 4.94 mmol) in dry THF (20 cm3) was added dropwise. The mixture was stirred at room temperature overnight then evaporated to dryness and the residue triturated with water, aqueous potassium carbonate and water to give 1.4 g. of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6](=[O:26])[N:7]=[C:8]([C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=[C:12]([CH3:25])[CH:11]=3)[S:9][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6](=[O:26])[N:7]=[C:8]([C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[C:12]([CH3:25])[CH:11]=3)[S:9][C:4]=2[CH:3]=1
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)nc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC(=O)O)nc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
tert-Butyl 3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-methyl-2-pyridyl]propanoate (0.25 g, 0.61 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated, and the residue was recrystallized from hexane-tetrahydrofuran to give the titled compound (0.16 g, 74%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br.O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[C:11](=[O:16])[C:12]([F:15])([F:13])[F:14]
Reactant: COc1cc(Cl)cc(C(=O)C(F)(F)F)c1N
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Nc1c(O)cc(Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 102.1 %

Procedure:
To a stirred, cooled (0° C.) solution of 31.2 g (123 mmol) of 2'-amino-5'-chloro-3'-methoxy-2,2,2-trifluoroacetophenone in 150 mL of CH2Cl2 was added 550 mL (550 mmol) of 1M BBr3 in CH2Cl2 over 20 min. The dark solution was stirred 17 h at ambient temperature, re-cooled to 0° C., and fitted with a pressure-equalizing dropping addition funnel and a Claisen adapter connected by rubber tubing to a large water scrubber. The reaction was carefully quenched by dropwise addition of aqueous Na2CO3 until a pH of 7-8 was reached. The phases were separated, and the aqueous phase was extracted with 1 liter of 1:1 ether-hexanes. The combined organic phases were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure to afford 30.1 g (100%) of 2'-amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone as a chalky brown solid, mp 120°-122° C. 1H NMR (300 MHz, CDCl3) δ7.33-7.36(m, 1H); 6.88(d, 1H, J=1.8 Hz); 6.75(br. s, 2H); 5.78(br. s, 1H). High resolution mass spec: calculated for C8H6NO2ClF3 (M+H)+ : 240.0039, found: 240.0029.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)[NH2:2].[CH3:15][CH2:16][C:17](=O)[CH2:18][CH2:19][C:20](=O)[CH2:21][CH3:22]>C(O)(=O)C>[CH2:21]([C:20]1[N:2]([NH:1][C:3]2[N:4]=[N:5][C:6]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:7][CH:8]=2)[C:17]([CH2:16][CH3:15])=[CH:18][CH:19]=1)[CH3:22]
Reactant: NNc1ccc(N2CCOCC2)nn1
Reactant: CCC(=O)CCC(=O)CC
Solvent: CC(=O)O
Product: CCc1ccc(CC)n1Nc1ccc(N2CCOCC2)nn1
Temperature: 67 °C
Yield: 85.7 %

Procedure:
To 1.95 g (10 m moles) of 3-hydrazino-6-morpholino-pyridazine dissolved in 12 ml of acetic acid, 1.71 g (12 m moles) of 3,6-octanedione dissolved in 4 ml of acetic acid are added at room temperature. The mixture is heated at 67° C. for 2 hours and then evaporated to dryness under vacuum. The oily residue is dissolved in toluene and the solution is evaporated to dryness. The residue is slurried with ice-water and neutralized with sodium bicarbonate to yield 2.58 g of a solid product. Said material, after crystallization from isopropanol gives 1.25 g (42%) of the title product, melting at 186°-9° C. Elemental analysis, I. R., N.M.R. and mass spectra are in agreement with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][C:9]=1[CH3:29].[CH:30]1(B(O)O)[CH2:32][CH2:31]1>>[CH:30]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][C:9]=2[CH3:29])[CH2:32][CH2:31]1
Reactant: OB(O)C1CC1
Reactant: Cc1ccc(Nc2cnc(-c3ccccc3Cl)c(C)c2)c(C(=O)OC(C)(C)C)c1
Product: Cc1ccc(Nc2cnc(-c3ccccc3C3CC3)c(C)c2)c(C(=O)OC(C)(C)C)c1

Procedure:
Obtained (0.152 g, 63% of yield) following the procedure described in Example 14 (step C) starting with tert-butyl 2-(6-(2-chlorophenyl)-5-methylpyridin-3-ylamino)-5-methylbenzoate (0.49 mmol, 0.200 g) and cyclopropylboronic acid (1.47 mmol, 0.126 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33][CH3:34])[CH:30]=[CH:31][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]([CH3:34])[C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=3)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:30]=[CH:31][CH:32]=1
Reactant: CNc1cccc(Cl)c1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(Cl)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (3-chloro-phenyl)-methyl-amine (50 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (3-chloro-phenyl)-methyl-amide: MS m/z: (M+H) 537.9.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl.C1COCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C:24](=[O:26])[CH3:25])[CH2:18][CH2:19]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Reaction time: 2 h

Procedure:
C-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazole-2-yl]-cyclohexyl}-methylamine (326 mg, 1.0 mmol, from Example 1C) and TEA (102 mg, 1.0 mmol) were dissolved in CH2Cl2/THF (1:1) and brought to 0° C. with an ice bath. Acetyl chloride (79 mg, 1.0 mmol) was added to the reaction mixture slowly and the ice bath was removed. After 2 hours, the solution was diluted with CH2Cl2, added to a separatory funnel and washed with 10% NaOH (3×). The solution was dried (Na2SO4), concentrated under reduced pressure, and the residue purified using flash chromatography (5%→10% MeOH/CH2Cl2) to give (N-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-acetamide.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2cccs2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-5-(2-thienyl)-2,4-pentadienoic acid (1.76 g) and 4-nitrophenol (1 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (1.24 g). The mixture was stirred at room temperature for 18 hours then, after the usual work up, the ester was crystallized from 2-propanol to yield 1.45 g of (2E,4Z)-5-(4-methoxyphenyl)-5-(2-thienyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 113°-115° C. A sample was recrystallized from 2-propanol to give the analytical specimen, mp 114.5°-115.5° C.