Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:57][O:58][C:59](=[O:67])[C:60]1[CH:65]=[CH:64][C:63]([NH2:66])=[N:62][CH:61]=1>ClCCl>[CH3:57][O:58][C:59](=[O:67])[C:60]1[CH:65]=[CH:64][C:63]([NH:66][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:62][CH:61]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC(Oc3c(F)cccc3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A solution of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (as prepared in Example 45, 200 mg, 0.62 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (345 mg, 0.74 mmol), N,N-diisopropylethylamine (240 mg, 1.85 mmol) and 6-aminonicotinic acid methyl ester (115 mg, 0.74 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-nicotinic acid methyl ester (57 mg, 20%) as a light yellow solid: LR-ES-MS m/z calculated for C23H23F2N3O5 [M]+ 459, observed [M+H]+ 460; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.9 Hz, 3H) 0.94 (d, J=6.9 Hz, 3H) 1.39-1.74 (m, 2H) 1.73-1.92 (m, 1H) 3.86 (s, 3H) 4.32 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.95-5.05 (m, 1H) 5.06 (s, 1H) 7.25-7.53 (m, 3H) 8.17 (d, J=8.8 Hz, 1H) 8.29 (dd, J=8.8, 2.1 Hz, 1H) 8.87 (d, J=2.1 Hz, 1H) 11.34 (s, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([CH2:16][C:17]1[CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:19]([C:25]([OH:27])=O)=[C:20]([CH3:24])[NH:21][C:22]=1[CH3:23])([OH:15])=[O:14].[CH:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:39][CH:40]=1>O1CCCC1>[C:38]1([N:41]2[CH2:46][CH2:45][N:44]([C:25]([C:19]3[CH:18]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[C:17]([CH2:16][C:13]([OH:15])=[O:14])=[C:22]([CH3:23])[NH:21][C:20]=3[CH3:24])=[O:27])[CH2:43][CH2:42]2)[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC1=C(CC(=O)O)C(c2ccccc2Cl)C(C(=O)O)=C(C)N1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1=C(CC(=O)O)C(c2ccccc2Cl)C(C(=O)N2CCN(c3ccccc3)CC2)=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.1 g (6.5 mmol) of carbonyldiimidazole are added to 1.60 g (5 mmol) of 5-carboxymethyl-4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylic acid suspended in 20 ml of absolute tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes and at a reflux temperature for 30 minutes. 1.62 g (10 mmol) of phenylpiperazine in 5 ml of absolute tetrahydrofuran are added to the resulting solution. This mixture is heated to reflux for 3.5 hours and then evaporated, the residue is taken up in methylene chloride, and the solution is washed successively with 1N hydrochloric acid, 1N sodium hydroxide solution and water, dried with magnesium sulphate and again evaporated. The residue crystallizes from isopropanol.
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].[C:31]([O:34][CH2:35][C:36](=O)[CH2:37]Cl)(=[O:33])[CH3:32]>CC(C)=O>[C:31]([O:34][CH2:35][C:36]1[CH2:37][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:6])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(=O)CCl
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(COC(C)=O)CSC=N2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 105.4 %

Procedure:
To a stirring solution of p-methoxybenzyl α-thioformamido-diethylphosphonoacetate (114 mg., 0.3 mmole) in acetone (1.5 ml.) is added powdered potassium carbonate (124 mg., 0.9 mmole). The resulting mixture is stirred for 5 minutes at room temperature and under a nitrogen atmosphere, then treated with a solution of 1-acetoxy-3-chloro-2-propanone (48 mg., 0.32 mmole) in acetone (0.5 ml.). After having been stirred for 3 hours at room temperature, the mixture is filtered to remove the salts which are washed with acetone. The combined filtrate and washings are evaporated in vacuo to a dark oil. The residue is dissolved in carbon tetrachloride (6 ml.), washed with aqueous phosphate (1 ml. of 1M dipotassium phosphate + 2 ml. water) and water (2 × 3 ml.), dried over magnesium sulfate, and evaporated in vacuo to give crude p-methoxybenzyl 5-acetoxymethyl-6H-1,3-thiazine-4-carboxylate (106 mg.) as an organic oil.
Reaction SMILES: I.[CH:2]12[CH2:13][CH2:12][CH:5]([CH2:6][CH:7]1[C:8]([O:10]C)=[O:9])[CH2:4][NH:3]2.[CH3:14][N:15]1[CH:19]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:17]=[CH:16]1>>[CH3:14][N:15]1[CH:19]=[C:18]([S:20]([N:3]2[CH2:4][C@H:5]3[CH2:12][CH2:13][C@@H:2]2[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6]3)(=[O:22])=[O:21])[N:17]=[CH:16]1
Reactant: COC(=O)C1CC2CCC1NC2
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: I
Product: Cn1cnc(S(=O)(=O)N2C[C@H]3CC[C@@H]2[C@H](C(=O)O)C3)c1

Procedure:
The title compound was synthesized as in Production Example 1, using methyl 2-azabicyclo[2.2.2]octane-6-carboxylate hydroiodide and 1-methyl-1H-imidazole-4-sulfonyl chloride as the raw material.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][N:21](C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[CH:26]([N:28]([CH3:30])N)=[O:27].C1CCN2C(=NCCC2)CC1>C(O)C>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[N:21]([N:28]([CH:26]=[O:27])[CH3:30])[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: CN(N)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(N(C)C=O)c2nc3cc(Cl)c(F)cc3cc2c1=O
Yield: 86.9 %

Procedure:
The 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthpyridine is prepared under the conditions of Example 1 but starting from 19.25 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate, 4.05 g of N-formyl-N-methylhydrazine and 1.6 g of DBU in 200 cm3 of ethanol. 16.4 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methyl-amino)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a colorless solid melting at 296°-298° C., which is used for the subsequent steps without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][C:4]1[CH:3]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c2ccc(CO)cc2n1
Yield: 89.7 %

Procedure:
(4-Chloro-2-methyl-quinolin-7-yl)-methanol (750 mg, 3.61 mmol) was refluxed in pyrrolidine (6.42 g, 90.3 mmol) for 16 h. Most of the pyrrolidine was then removed under reduced pressure, the oily residue was taken up in toluene, evaporated, and the solid obtained triturated in ethyl acetate, filtered and dried to afford the title compound (785 mg, 90%). Light brown solid, ISP-MS: m/e==243.3 ([M+H]+).
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[Br:9][C:10]1[CH:18]=C[C:13]([C:14]([OH:16])=[O:15])=[C:12](C)[CH:11]=1.CI>C1COCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[C:8]([CH2:6][CH3:7])[CH:18]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of LDA (10.7 mL, 21.39 mmol) in THF (20 mL) was added 4-bromo-2-methylbenzoic acid (2 g, 9.3 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 1 h, cooled to −70° C., and then MeI (2.3 mL, 37.20 mmol) was added dropwise. The mixture was allowed to warm up to 0° C., stirred for 3 h, then quenched with H2O, and the pH was adjusted to 1-2 with 3 N HCl. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-ethylbenzoic acid as a white solid.
Reaction SMILES: CC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]([F:43])[CH:34]=3)[N:29]=2)=[CH:24][C:23]=1[CH2:44][O:45][CH3:46].[CH3:47][O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1B1OC(C)(C)C(C)(C)O1>>[F:43][C:35]1[CH:34]=[C:33]([C:30]2[N:29]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=4[O:48][CH3:47])=[C:23]([CH2:44][O:45][CH3:46])[CH:24]=3)[O:32][N:31]=2)[CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]
Reactant: COc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1Br
Agent: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1-c1ccccc1OC

Procedure:
Title compound was prepared following procedure and work up described for Intermediate 5 step 2 but starting from methyl 4-{5-[4-bromo-3-(methoxymethyl)phenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate obtained from step 1 (50 mg, 0.12 mmol) and 2-(2-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.5 mg, 0.13 mmol) (130° C. for 10 min under microwave irradiation). Purification by flash chromatography (cHex:EtOAc, from 100:0 to 20:80) gave the title compound as a yellow powder. LC/MS (Method B): 449.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:23][N:24]([CH3:41])[CH2:25][CH2:26][CH2:27][N:28]([CH3:40])[C:29]1[C:30]([NH2:39])=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.C1COCC1>C(N(CC)CC)C>[CH3:41][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][N:28]([CH3:40])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:30]=1[NH:39][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(Cl)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1NC(=O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 25 °C
Reaction time: 108 h

Procedure:
To 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoyl chloride (60 mg, 0.17 mmol) and N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (44.1 mg, 0.160 mmol) was added THF (1.0 mL). The mixture was stirred at rt for 4.5 days. The reaction was quenced with excess triethylamine, filtered and concentrated. The residue was purified by Gilson reverse-phase HPLC (0.1% TFA in water/acetonitrile). After basic workup, N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzamide was obtained as a white solid. MS m/z=558 [M+1]+. Calc'd for C28H27F4N5O3: 557.55.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[NH3:12]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH2:12])=[O:7])=[CH:4][N:3]=1
Reactant: N
Reactant: COC(=O)c1ccc(C)nc1
Product: Cc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of methyl 6-methylnicotinate (13.9 g) and 28% aqueous ammonia (140 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 8.98 g, 72%).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:25])[O:6][CH2:7][C:8]1([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]=[C:9]1[O:18][CH3:19])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:27].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[CH:1]([NH:4][C:5](=[O:25])[O:6][CH2:7][C:8]1([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[CH:10]=[C:9]1[O:18][CH3:19])([CH3:3])[CH3:2]
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Yield: 83.5 %

Procedure:
To a solution of Example 180A (39 mg, 0.11 mmol) in benzene (1 mL) was added celite (39 mg), pyridinium dichromate (0.17 g, 0.45 mmol), and a solution of 70% t-butyl peroxide in water (58 μL, 0.45 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (3 mL), washed with 5% Na2S2O5 (3 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (10%-20% ethyl acetate/hexane) afforded product as a white solid (33 mg, 83%). 1H NMR (300 MHz, CDCl3) δ ppm 0.53 (m, 1 H), 0.75 (m, 7 H), 0.93 (d, J=5.88 Hz, 3 H), 1.03 (d, J=5.88 Hz, 3 H), 1.34 (m, 1 H), 1.79 (m, 1 H), 2.08 (m, 1 H), 3.84 (s, 3 H), 4.13 (m, 1 H), 4.41 (d, J=10.30 Hz, 2 H), 4.57 (m, 1 H), 5.96 (s, 1 H), 7.43 (m, 2 H), 7.59 (m, 1 H), 8.19 (d, J=7.72 Hz, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:3][CH2:4][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
According to a method similar to that described in Zhur. Obschei Khim., vol. 32, pp 835-41 (1953), 3,4-diaminobenzoic acid was prepared. A formic acid solution (200 ml) of 3,4-diaminobenzoic acid (8 g) thus prepared was refluxed for 4 hrs to yield 5-carboxybenzimidazole.hydrochloride (8.9 g). The carboxylic acid (8.9 g) was refluxed with heating for 3.5 hrs in a mixture of sulfuric acid (4 ml) and absolute ethanol (140 ml) to yield 5-ethoxycarbonylbenzimidazole (mp. 93°-94° C., 7.8 g). An anhydrous tetrahydrofuran solution (20 ml) of the ester (7.5 g) was added to an anhydrous tetrahydrofuran suspension (50 ml) of lithium aluminium hydride (6.5 g) while cooling. The mixture was stirred for 3 hrs at room temperature to yield 5-hydroxymethylbenzimidazole (mp. 128.4° C., 3.62 g). A 47% aqueous hydrobromic acid solution (33 ml) containing the benzimidazole derivative (2.2 g) and cysteamine hydrochloride (1.9 g) was refluxed with heating for 7 hrs to yield 5-[(2-aminoethyl)thiomethyl]benzimidazole.2 hydrobromide (mp. 224°-225° C., 4.2 g).
Reaction SMILES: [CH2:1]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:1]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCc1cn(CCCC(=O)OCC)c2ccccc12
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCc1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-(3-linoleyl-1-indolyl)butyrate obtained in Ex. 27 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give 4-(3-linoleyl-1-indolyl)butyric acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.Br[C:11]1[C:12]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])(=[O:21])=[O:20])=[N:13][CH:14]=[C:15]([CH3:17])[N:16]=1>>[Cl:29][C:23]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:12]1[C:11]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:16][C:15]([CH3:17])=[CH:14][N:13]=1)(=[O:20])=[O:21]
Reactant: Cc1cccc(CO)n1
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Product: Cc1cccc(COc2nc(C)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)n1

Procedure:
Prepared by the method of Example 20 using 6-methylpyridine-2-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.023 g.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1.[C:26]([O:30][C:31](=[O:38])[CH2:32][C@H:33]([NH2:37])[C:34]([NH2:36])=[O:35])([CH3:29])([CH3:28])[CH3:27].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:4][O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:15])(=[O:14])[NH:37][C@H:33]([C:34](=[O:35])[NH2:36])[CH2:32][C:31]([O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:38])=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(N)=O
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a room temperature CH2Cl2 solution (400 mL) of 3-benzyloxy-4-chlorosulfonyl-benzoic acid methyl ester (11.43 g, 33.50 mmol) was added (S)-3-amino-succinamic acid tert-butyl ester (6.32 g, 33.50 mmol) and pyridine (10.80 mL). The reaction mixture was allowed to stir for 12 h at room temperature. The reaction was then diluted with ethyl acetate and washed with 5% citric acid and saturated NaHCO3. The organic phase was dried (MgSO4), and then the solvent was removed under vacuum. The resulting crude product was purified using silica gel flash chromatography (3% MeOH in CH2Cl2). 3-Benzyloxy-4-((S)-2-tert-butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-benzoic acid methyl ester was obtained in 45% yield (7.40 g) as an off white foam. MS m/z 491.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: COc1ccc(N)cc1
Reactant: O=Cc1ccccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(NCc2ccccc2Cl)cc1

Procedure:
A solution of 2-chlorobenzaldehyde (70 g.) and 4-methoxyaniline (61.5 g.) in toluene (750 ml.) was refluxed under a Dean and Stark separator until no more water collected (ca. 1 hour). The toluene was evaporated in vacuo, and the residue was dissolved in methanol (1.5 l.). The methanolic solution was treated at room temperature with sodium borohydride (60 g.) added portionwise so that, with gentle cooling, the temperature was maintained at 40°-50° C. The solution was then refluxed for 15 minutes, diluted with water (1.5 l.), and the aqueous mixture extracted with ether (3×200 ml.). The combined ethereal extracts were washed with water (2×100 ml.), dried (K2CO3), and evaporated to give N-(4-methoxyphenyl)-2-chlorobenzylamine as a brown oil, Infra Red ν max 3400, 1618 cm.-1, which was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:18]1C=C2C(=CC=1C)N(C(OC(C)(C)C)=O)N=C2.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([CH3:18])[CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccc2[nH]ncc2c1
Reactant: Cc1cc2c(cnn2C(=O)OC(C)(C)C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(-c2cccnc2Cl)cc2cn[nH]c12

Procedure:
5-(2-Chloropyridin-3-yl)-7-methyl-1H-indazole was synthesized in the similar manner to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of tert-butyl 5-bromo-6-methyl-1H-indazole-1-carboxylate (1.4 g, 4.5 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.4 g, 5.9 mmol), Pd(PPh3)4 (370 mg, 0.32 mmol) and 2M aq.Na2CO3 (7 mL, 14 mmol) in 1,4-dioxane (40 mL). Upon work-up and purification procedure used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole provided white solid of 5-(2-chloropyridin-3-yl)-7-methyl-1H-indazole (840 mg, 73%). 1H NMR (DMSO-d6): δ 13.28 (s, 1H), 8.40 (dd, 1H, J=1.7 and 4.7 Hz), 8.11 (app d, 1H, J=1.2 Hz), 7.87 (dd, 1H, J=1.7 and 7.6 Hz), 7.64 (s, 1H), 7.49 (dd, 1H, J=4.7 and 7.6 Hz), 7.19 (s, 1H), 2.54 (s, 3H).LCMS: rt 6.41 min (A), purity 98%, MS (m/e) 244 (MH+)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[N:25]1([C:23](=[O:24])[CH:22]=[CH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)N3CCOCC3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(C=Cc1ccc(OC2CCNCC2)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
A solution of 3-[2-(1-t-Butyloxycarbonyl piperidin-4-yloxy)pyridin-5-yl]-1-(morpholin-4-yl)prop-2-ene-1-one (0.7 grams, 0.0016 moles) in dichloromethane (20 mL) was treated with trifluoroacetic acid (1.3 mL, 0.016 moles) at room temperature. The reaction mass was stirred for 6 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mass was poured on to chilled water (30 mL) and basified with 40% lye solution (pH˜9). The layers were separated and the aqueous layer was further extracted with dichloromethane (2×20 mL). The combined organic phase was washed with water (30 mL), brine solution (30 mL) and dried over sodium sulphate. The organic phase was concentrated on rotavacuum to afford the title compound (0.48 grams).