Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[Cl:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1O.Cl.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:33][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]([O:32][CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]5[Cl:34])=[O:31])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=C(O)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Reactant: OC1CCCCC1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(OC1CCCCC1Cl)C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Reaction time: 8 h

Procedure:
To a solution of 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid (E, 160 mg) in dichloromethane (5 ml) are added, at room temperature, 2-chlorocyclohexanol (57 mg), 4-dimethylaminopyridine (4 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (94 mg). The mixture is stirred overnight, and water is then added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solids are filtered off and the solvent is distilled off. The residue is purified by chromatography. This gives 2-chlorocyclohexyl 3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazole-5-carboxylate (100 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C@H:13]2[CH2:18][CH2:17][C@@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][C@H:13]1[CH2:14][CH2:15][C@@H:16]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:18]1
Reactant: Cc1nc(O[C@H]2CC[C@@H](C(C)C)CC2)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1nc(O[C@H]2CC[C@@H](C(C)C)CC2)c(Br)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
To a stirred solution of 3-bromo-2-(cis-4-isopropylcyclohexoxy)-6-methyl-5-nitro-pyridine (22.59 g, 63.24 mmol) in EtOH/H2O (600 mL/150 mL, 4/1 v/v), ammonium chloride (3.45 g, 63.24 mmol, 1.0 eq) and iron powder (14.27 g, 253.0 mmol, 4 eq) were added at room temperature under inert atmosphere (Ar). The reaction mixture was stirred for 3 h under heating to reflux. As TLC indicated that the starting material was consumed at this point in time, the reaction mixture was cooled to room temperature and filtered through a pad of celite. The resulting filtrate was concentrated in vacuo and the residue partitioned between a 2 molar aqueous NaOH solution (100 mL) and ethyl acetate (150 mL). After phase separation, the aqueous phase was extracted once more with ethyl acetate (2×100 mL). The organic layer was washed with brine (400 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to afford the title compound (21.01 g, 101%) in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:10]1[CH2:14]OC[CH2:11]1>>[CH3:1][C:2]1[S:3][C:4]([CH:8]([OH:9])[CH:10]([CH3:14])[CH3:11])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C=O)s1
Reactant: C1CCOC1
Product: Cc1nc(C)c(C(O)C(C)C)s1
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dimethylthiazole-5-carbaldehyde (1.07 g, 7.58 mmol) in THF (12 mL) was cooled to 0° C. Isopropyl magnesium chloride LiCl complex (1.3 M in THF, 6 mL, 8.8 mmol) was then added dropwise. After 30 minutes, the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to afford an orange oil. Chromatography on silica gel (5% acetone-DCM increasing to 30% acetone) provided the title compound as a light amber oil.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[CH:17]=[CH:18][C:19](=[O:21])[CH3:20]>CS(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[C@@H:17]1[CH2:2][C@H:18]1[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)C=Cc1c(Cl)cccc1Cl
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)[C@@H]1C[C@H]1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A round bottom flask equipped with magnetic stirrer, nitrogen inlet and additional funnel was charged with trimethylsulfoxonium iodide (1.1 g, 5.02 mmol), DMSO (10 ml) and powdered sodium hydroxide (0.175 g, 4.39 mmol). The suspension was stirred for 1.5 hours at ambient temperature to yield a solution. So prepared solution was added drop wise at ambient temperature to a solution of 4-(2,6-dichloro-phenyl)-but-3-en-2-one (0.90 g, 4.18 mmol) prepared as described in example P31 in DMSO (5 ml). The reaction mixture was stirred for 0.5 hours, poured onto ice and extracted with ether (3×25 ml). Combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (25 g) (eluent: n-hexane/ethyl acetate 20:1) to afford 0.30 g (31% of theory) of trans 1-[2-(2,6-dichloro-phenyl)-cyclopropyl]-ethyanone in form of a pale yellow liquid.
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]([O:20][C:21]([NH:23][CH2:24][P:25]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:27])[OH:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O)C>C1COCC1>[C:16]([O:20][C:21]([NH:23][CH2:24][P:25]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:26])[O:27][CH2:1][CH3:2])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCP(=O)(O)CNC(=O)OC(C)(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
DCC (190 mg, 0.92 mmol) in THF (4 ml) is added dropwise in the course of 4 minutes to a solution of the phosphinic acid 1 (270 mg, 0.83 mmol) in dry THF (4 ml) and abs. ethanol (0.30 ml, 5.15 mmol) which is boiling under reflux. After 1.5 hours (checking by TLC), the reaction solution is cooled to room temperature and filtered. The filter residue is washed with ether. The filtrate is extracted with water (2×20 ml). The organic phase is dried over Na2SO4 and concentrated under reduced pressure. After purification by column chromatography on silica gel (ethyl acetate/heptane=3:2), the phosphinic acid ester 3 (100 mg, 34% of theory) is obtained. M.p. 117.5°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]([C:18]#[N:19])([CH3:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:29][OH:30]>C(O)C>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]([C:18](=[NH:19])[NH:29][OH:30])([CH3:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)(CS(C)(=O)=O)NC(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(CS(C)(=O)=O)(NC(=O)OCc1ccccc1)C(=N)NO
Temperature: 60 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
To a solution of (1-Cyano-2-methanesulfonyl-1-methyl-ethyl)-carbamic acid benzyl ester (Example 109a, 3.07 g, 10.4 mmol) in dry ethanol (58 ml) were added triethylamine (2.17 mL, 15.5 mmol) and hydroxylamine hydrochloride (936 mg, 13.5 mmol). The reaction mixture was then stirred at 60° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a ethyl acetate/heptane gradient to yield the title compound (2.04 gr, 60%) as a white powder. MS (ESI, m/z): 330.6 (M+H+).
Reaction SMILES: [O:1]1[C:5]2([CH2:16][CH2:15][CH2:14][C:7]3([CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8]3)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:1]1[C:5]2([CH2:16][CH2:15][CH2:14][C:7]3([CH2:11][CH2:10][CH:9]([CH2:12][O:13][S:23]([C:20]4[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=4)(=[O:25])=[O:24])[CH2:8]3)[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OCC1CCC2(CCCC3(C2)OCCO3)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC3(CCCC4(C3)OCCO4)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (1,4-dioxa-dispiro[4.1.4.3]tetradec-9-yl)methanol (14a) (1.20 g, 5.3 mmol) in dry pyridine (12 mL) at 0° C. was added 4-dimethylamino-pyridine (catalytic amount) and p-toluenesulfonyl chloride (2.04 g, 10.6 mmol). The reaction mixture was stirred at room temperature for 24 hours and then poured into a 2 M HCl solution (50 mL). The aqueous solution was extracted with CH2Cl2 and the combined organic layers were washed with a 2 M HCl solution and then with a saturated K2CO3 solution. After drying over anhydrous MgSO4, the solvent was removed in vacuo to afford the desired product as a colorless oil which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2.[N+:17]([O-])([OH:19])=[O:18].C(OCC)C>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C1CCc2c(cccc2OC)C1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COC(=O)C1CCc2c(OC)ccc([N+](=O)[O-])c2C1
Temperature: 0 °C
Yield: 20 %

Procedure:
Methyl 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.1 g, 5 mmol; described in: Johnson, D. W.; Mander, L. N. Aust. J. Chem. 1974, 8, 1277-1286) dissolved in acetic anhydride (20 mL), was treated with 70% nitric acid (0.4 mL) at 0° C. for 1 h and the mixture was poured into ice-water and diethyl ether. The organic phase was separated, evaporated in vacuo and the residue triturated with diisopropyl ether to yield 0.27 g (20%) of the title compound as crystals: mp 100-104° C.; EIMS (70 eV) m/z (relative intensity) 265 (35, M+).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:28]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>O1CCCC1>[CH2:47]([N:46]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COc1ccc(C=O)cc1

Procedure:
To a 100 mL solution of freshly distilled tetrahydrofuran (THF) was added p-formylphenoxyacetic acid (K & K Labs) (MW 180, 0.540 g, 3.0 mmol), triethyl amine (MW 101.19, 0.333 g, 3.3 mmol) and trimethylacetyl chloride (MW 120.57, 0.398 g, 3.3 mmol). After 20 minutes of heating at reflux, dioctadecylamine (Fluke) (MW 522.01, 1.723 g, 3.3 mmol) was added. The reaction was refluxed overnight.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][S:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:24]Br>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:14]([Br:24])[S:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: BrBr
Reactant: COc1ccc(-c2cscc2-c2ccc(S(C)(=O)=O)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)csc2Br)cc1
Reaction time: 0.25 h

Procedure:
3-(4-methylsulphonylphenyl)-4-(4-methoxyphenyl) thiophene from Example 6 (9.3 mg) was dissolved in acetic acid (10 ml) and heated to 90° C. at which time Br2 in acetic acid (1.0 M, 27 μl) was added in one portion. The reaction was stirred for 15 minutes at which time the solvent was removed at reduced pressure. The residue was dissolved in a minimum of ethyl acetate and chromatographed on silica, eluting with 2.5% isopropanol in hexane, yielding 3-(4-methylsulfonylphenyl)-4-(4-methoxyphenyl)-5-bromothiophene. CI MS (M+H):423/425.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]([C:34]1[CH:35]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1)#[N:33]>>[C:32]([C:34]1[CH:35]=[C:36]([S:40]([NH:43][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:15][CH:16]=2)=[O:31])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1)#[N:33]
Reactant: N#Cc1cccc(S(N)(=O)=O)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(C#N)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-cyanobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.26-8.21 (2H, m), 7.86 (1H, d, J=7.9 Hz), 7.68 (1H, t, J=7.9 Hz), 7.46-7.20 (9H, m), 6.01 (1H, br.s), 3.48-3.42 (2H, m), 2.84 (2H, t, J=6.3 Hz), 2.32 (3H, s), 2.21 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](/[C:21](=[N:23]/[OH:24])/[CH3:22])[CH:16]=2)([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[H-].[Na+].Cl.Cl[CH2:32][CH2:33][NH2:34]>CN(C=O)C>[NH2:34][CH2:33][CH2:32][O:24]/[N:23]=[C:21](/[C:17]1[CH:16]=[C:15]([C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:25]([O-:27])=[O:26])[CH:4]=2)=[O:10])([CH3:14])[CH3:13])[CH:20]=[CH:19][CH:18]=1)\[CH3:22]
Reactant: C/C(=N\O)c1cccc(C(C)(C)NC(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)c1
Reactant: NCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C(=N\OCCN)c1cccc(C(C)(C)NC(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
(E)-1-(4-Chloro-3-nitrophenyl)-3-(2-(3-(1-(hydroxyimino)ethyl)phenyl)propan-2-yl)urea (7b, 100 mg, 0.25 mmol) in 3 mL dry DMF was added drop wise at 0° C. to sodium hydride dispersion in mineral oil (15.3 mg, 0.50 mmol). The resulting mixture was stirred at 0° C. for 30 min. 2-Chloroethylamine hydrochloride (29.6 mg, 0.25 mmol) in 2 mL DMF was added and the reaction mixture was stirred at room temperature for 2 h and then the volatiles were removed under reduced pressure. The residue was dissolved in a minimal amount of methanol and purified by column chromatography using methanol/chloroform to obtained 9 (49 mg, 46%) 1H NMR (DMSO-d6, 400 MHz) δ 1.61 (s, 6H), 2.19 (s, 3H), 2.79 (t, J=5.6 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 6.95 (s, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.42-7.47 (m, 3H), 7.56 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 8.20 (d, J=2 Hz, 1H), 9 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 13.3, 30.1, 41.6, 55.4, 76.6, 113.8, 116.2, 122.7, 122.9, 124.5, 126.3, 128.8, 132.2, 136.5, 141.1, 148.1, 148.8, 154.2, 154.9; ESI-HRMS for C20H24Cl N5O4 (M+H)+ calcd. 434.1595. found. 434.1595.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: NCCN1CCCC1=O
Product: COc1cc(NCCN2CCCC2=O)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 89 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using 1-(2-amino-ethyl)-pyrrolidin-2-one instead of thiomorpholine to the title compound (231 mg, 89%) which was obtained as an off-white solid. MS: m/e=478.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][C:20]([F:21])=[C:13]([Cl:12])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(F)c(Cl)c1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(F)c(Cl)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
To the mixture of 6-chloro-2-oxindole (5.3 g, 32 mmol) (Crescent) and 3-chloro-4-fluorobenzaldehyde (5 g, 32 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.7 g, 32 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 8 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([F:30])[CH:23]=1
Reactant: COc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.8 %

Procedure:
To a solution of 4-bromo-6-(methyloxy)-1H-indazole (200 mg, 0.88 mmol) in dichloromethane (10 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (433 mg, 1.76 mmol), pyridine (0.14 mL, 1.73 mmol), copper acetate (239 mg, 1.32 mmol) and powdered 4A molecular sieves (500 mg). The reaction mixture was stirred at room temperature in the presence of air for 3 days. Celite was added to the mixture then the mixture was filtered through a pad of celite and then the filtrate concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-80% dichloromethane in hexane to yield the title compound (D3) (176 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14](Cl)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1B(O)O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CO.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:22]1[C:21]([Cl:20])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:27])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: Clc1ccc2cc(OCc3ccccc3)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1-c1ccc2cc(OCc3ccccc3)ccc2n1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 3 g of 6-(benzyloxy)-2-chloroquinoline 12 in toluene (294 ml) is added Pd(PPh3)4 (1 g). After 30 minutes, a solution of 2,6-dichlorophenylboronic acid (4.22 g) in methanol (186 ml) and 120 ml of a saturated aqueous solution of NaHCO3 is added. The reaction is heated under reflux for 4 h. After evaporation, the aqueous phase is extracted with AcOEt (3×20 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated to dryness. The residue is purified over silica gel using AcOEt/petroleum ether 5/95 then 10/90 as eluent to give 6-(benzyloxy)-2-(2,6-dichlorophenyl)quinoline 19 as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)[CH:3]=1.O.NN>C(O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCN
Yield: 86.3 %

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[3-(phthalimide)propoxy]benzamide (4.73 g, 10 mmoles) (prepared in Example 38), 64% hydrazine hydrate (800 mg, 16 mmoles) and absolute ethanol (15 ml) was heated briefly to reflux until clear solution was formed. The solution was heated 16 hours at 55°-57° C. and then 2 hours at reflux. After cooling, a solid was filtered off and washed with ethanol. The combined filtrate and washings were concentrated in vacuo. The residue was dissolved in methylene chloride, and insoluble solid removed by filtration. The filtrate was washed with water, dried and concentrated in vacuo to give a solid product. This was recrystallized from methylene chloride-n-pentane to give 2.96 g (86.3%) of the title compound as white solid, mp 119°-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:9]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:34][C:35]=2[CH3:36])[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3nc(-c4ccccc4)oc3C)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
After a mixture of ethyl 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (621 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2.5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (439 mg, yield: 74%). This was recrystallized from ethanol-hexane. Melting point: 126–127° C.