Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.C([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)(OCC1C=CC=CC=1)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N:32]1([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:8])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Nc1ccccc1N1CCCCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (9.8 mL) at -78° C. under N2 is treated with sec-butyllithium (1.3M in cyclohexane, 3.64 mL) dropwise over 3 mins, and the resulting mixture is stirred at -78° C. for 2 hrs. The mixture is then treated with a solution of N-(carbobenzyloxy)-4-piperidone (919 mg) in dry tetrahydrofuran (3.9 mL) dropwise over 2 mins and is stirred at -78° C. for 2 hrs. The mixture is then warmed to -20° C. over 1 hr and quenched with saturated aqueous ammonium chloride (5 mL), diluted with water (20 mL), the layers are separated, the aqueous phase is extracted with diethyl ether (20 mL), and the combined organic phase is washed with saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (15 mL) and treated with anhydrous potassium carbonate (544 mg, 3.94 mmol), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with diethyl ether (30 mL), washed with water (20 mL) and saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 4-hydroxy)piperidinyl benzenamine intermediate (Rf =0.25 by TLC, ethyl acetate/hexane (50/50). A mixture of this intermediate and N,N-dimethylaniline (1.00 mL) in tetrahydrofuran (20 mL) is cooled to -20° C. and treated with benzyl chloroformate (0.59 mL), and the resulting mixture is stirred at -20° C. for 1 hr. The mixture is then diluted with saturated aqueous potassium carbonate (5 mL), water (25 mL) and diethyl ether (25 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with a gradient of ethyl acetate/hexane (25/75-50/50), and those fractions with an Rf =0.47 by TLC (ethyl acetate/hexane, 50/50) are pooled and concentrated to give the title compound, NMR (400 MHz, CDCl3) 7.35, 7.00, 6.92, 5.20, 5.16, 4.10, 3.32, 2.15 and 1.79 δ and Anal. calculated for C27H27FN2O5 : C, 67.77; H, 5.69; N, 5.85. Found: C, 67.44; H, 5.83; N, 5.65.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35](=[O:37])[NH2:36])=[CH:32][CH:33]=4)[N:28]([CH3:38])[CH:27]=3)[C:23](O)=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1.CN(C1C=CC=CN=1)C.[C:48]1([CH3:58])[CH:53]=[CH:52][C:51]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:50][CH:49]=1>ClCCl.CN(C)C=O>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([NH2:36])=[O:37])=[CH:32][CH:33]=4)[N:28]([CH3:38])[CH:27]=3)[C:23]([NH:57][S:54]([C:51]3[CH:52]=[CH:53][C:48]([CH3:58])=[CH:49][CH:50]=3)(=[O:55])=[O:56])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2ccc(C(N)=O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(N)=O)ccc23)cc1
Yield: 67.1 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol) was added to a stirred solution. 2-(1,3-benzodioxol-5-yl)-2-(6-carbamoyl-1-methyl-1H-3-indolyl)acetic acid (from step (f). 100 mg, 0.28 mmol), dimethylaminopyridine (45 mg, 0.37 mmol) and p-toluenesulphonamide (53 mg, 0.31 mmol) in dichloromethane (5 ml) and dimethylformamide (1 ml) at room temperature under a nitrogen atmosphere. After 14 h the solvent was removed in vacuo and the product was extracted from 1N hydrochloric acid (50 ml) with ethyl acetate (2×50 ml). The organic layers were dried and concentrated to give a fawn foam. Flash column chromatography (elution with 95% dichloromethane/5% methanol) gave the product (95 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([NH:25][C:22](=[O:24])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: Nc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)Nc1ccccc1

Procedure:
Using N-(tert-butoxycarbonyl)-(O-tert-butyl)-L-tyrosine and aniline, and in the same manner as in the method described in Example 1 (3), synthesis was performed.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[Li]CCCC.[CH3:17][C:18]1([CH3:35])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][CH2:24][C:25]3=O)=[CH:20][C:19]1=2>C1COCC1>[CH3:32][C:29]1([CH3:33])[CH2:30][CH2:31][C:18]([CH3:35])([CH3:17])[C:19]2[CH:20]=[C:21]3[C:26]([CH2:25][CH2:24][CH:23]=[C:22]3[CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:27][C:28]1=2
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)CCCC3=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CC1=CCCc2cc3c(cc21)C(C)(C)CCC3(C)C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of trimethyl phosphonoacetate (5.68 g, 31 mmol) in THF (15 ml) was added dropwise nBuLi (9.3 ml, 2.5 M, 23 mM) at 0° C., and the resulting solution was stirred at that temperature for 30 min. 3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthracen-1-one (2.0 g, 7.8 mmol) in THF (10 ml) was added at 25° C., and the mixture was stirred at that temperature for 30 min. Standard work-up procedures as detailed in Example 1, followed by purification of the product by column chromatography (10% ether in hexane) gave methyl (3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethylanthracen-1-yl)acetate (1.33 g, 55%): 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, ArH), 7.04 (s, 1H, ArH), 5.94 (br t, 1H, olefinic), 3.68 (s, 2H, OCH3), 3.43 (s, 2H, CH2), 2.74 (t, J=7.9 Hz, 2H, CH2, benzylic), 2.31 (m, CH2, 2H, allylic), 1.66 (s, 4H, 2CH2), 1.27 (s, 12H, 4CH3).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][CH:6]=1.[CH2:17]([O:21][C:22]([NH:24][NH2:25])=[O:23])[CH:18]([CH3:20])[CH3:19]>CO>[CH2:17]([O:21][C:22]([NH:24][N:25]=[CH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])=[O:23])[CH:18]([CH3:20])[CH3:19]
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Reactant: CC(C)COC(=O)NN
Solvent: CO
Product: CC(C)COC(=O)NN=Cc1ccc2[nH]cc(CCN(C)C)c2c1
Reaction time: 6 h
Yield: 85.3 %

Procedure:
A 100 ml flask is charged with 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Reference Example 9; 2.16 g, 10 mmol), methanol (50 ml), and hydrazinecarboxylic acid isobutyl ester (1.32 g, 10 mmol). This mixture is heated at reflux, and after 6 hours the conversion is 70% by NMR. Heating is continued over night, and removal of the solvent gives the crude product, which is then filtered over a pad of silica (40 g) with the following eluent: CH2Cl2:methanol: NEt3 90:10:1 (v:v:v), ca. 700 ml. Removal of the solvent gives the product (2.82 g, 85%) as a pale yellow residue which is pure by NMR. 1H-NMR (CDCl3, 300 MHz) δ 0.93 (d, 6H, J=6.5 Hz, CH(CH3)2); 1.96 (m, 1H, CH(CH3)2); 2.22 (s, 6H, N(CH3)2); 2.52, 2.78 (2 m, 2H each, CH2CH2NHMe2); 3.97 (d, 2H, J=6.5 Hz, OCH2); 6.85 (s, 1H, H-2); 7.04 (d, 1H, J=7.6 Hz, H-7); 7.41 (dd, 1H, J=1.5 Hz, H-6); 7.61 (bs, 1H, H-4); 7.86 (br s, 1H, N═CH); 9.43 (br s, 1H, NH); 9.82 (br s, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 19.36 (CH(CH3)2); 23.59 (CH2); 28.39 (CH(CH3)2); 45.53 (N(CH3)2); 60.32 (CH2NMe2); 71.87 (OCH2); 112.20 (C-7); 114.21 (C-3); 119.35 (C-4); 120.58 (C-6); 123.41 (C-2); 125.17 (C-5); 127.48 (C-9); 137.76 (C-8); 146.80 (N═CH); 154.91 (NC═O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3OCC[O:22]3)=[CH:17][CH:16]=2)=[C:10]([F:26])[CH:9]=1)=[O:6]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=2)=[C:10]([F:26])[CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2ccc(C3OCCO3)cc2)c(F)c1)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: O=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2F)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
3,4-Dichloro-N-[4-(4-[1,3]dioxolane-2-ylphenoxy)-3-fluorophenyl]benzamide (17.4 g, 38.9 mmol) was added to 80% acetic acid, and the resulting solution was stirred for 1.5 hours at 80° C. The reaction solution was concentrated under reduced pressure, wherein the obtained residue was recrystallized from 80% ethanol to thereby yield 12.8 g of the title compound.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[C:11]3[O:13][CH2:14][O:15][C:10]3=[CH:9][C:8]=2[C:16]2([OH:23])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=N1.Cl>>[CH3:22][N:19]1[CH2:20][CH2:21][C:16]2([C:8]3[C:7](=[CH:12][C:11]4[O:13][CH2:14][O:15][C:10]=4[CH:9]=3)[C:4](=[O:5])[O:23]2)[CH2:17][CH2:18]1
Reactant: CN1CCC(O)(c2cc3c(cc2C2=NC(C)(C)CO2)OCO3)CC1
Agent: Cl
Product: CN1CCC2(CC1)OC(=O)c1cc3c(cc12)OCO3

Procedure:
Treatment of 4-[2-(4,4-dimethyl-2-oxazolin-2-yl)-4,5-methylenedioxyphenyl]-4-hydroxy-1-methylpiperidine with hydrochloric acid by the method described in Example 1d provides 1,3-dihydro-1'-methyl-5,6-methylenedioxyspiro-[isobenzofuran-1,4'-piperidine]-3-one.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:8]2[O:9][C:10]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:21][CH2:20]1
Reactant: Cc1cccc2nc(S)oc12
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(N3CCN(C)CC3)oc12
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (454 mg) was dissolved in anhydrous toluene (6 ml), the resulting solution was mixed with 2-mercapto-7-methylbenzoxazole (300 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (2.0 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)-7-methylbenzoxazole (392 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2B(O)O)[CH:21]=[CH:20][CH:19]=1>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[N:18]=[CH:19][CH:20]=[CH:21]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1cccc2cccnc12

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 8-quinoline boronic acid. Yield 0.356 g
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:22])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[N:26]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:12][C:11](=[O:22])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(C(=O)CC(=O)C(C)C(=O)c2ccccc2)c1
Reactant: Nc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cccc(-c2cc(=O)c(C)c(-c3ccccc3)n2-c2ccccc2F)c1
Yield: 51.7 %

Procedure:
To 30 ml of xylene were added 2.0 g (0.0068 mole) of 2-methyl-5-(3-methylphenyl)-1-phenyl-1,3,5-pentanetrione, 7.6 g (0.068 mole) of 2-fluoroaniline, 2.0 g (0.012 mole) of para-toluenesulfonic acid and 14.0 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 1 hour. After cooling the reaction mixture, solid matter was filtered off and the filtrate was mixed with 100 ml of chloroform and then washed successively with 50 ml of 10% hydrochloric acid, 50 ml of a 10% aqueous solution of sodium hyroxide and water. The filtrate was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was crystallized from a 1:3 mixed solvent of chloroform and hexane to give 1.3 g of 1-(2-fluorophenyl)-3-methyl-6-(3-methylphenyl)-2-phenyl-4-(1H)-pyridinone having a melting point of 211°-214° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][CH3:22])[CH:15]=1)[CH:7]=[C:6]([C:23]([O:25]CC)=[O:24])[C:5]2=[O:28].Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([O:21][CH3:22])[CH:15]=1)[CH:7]=[C:6]([C:23]([OH:25])=[O:24])[C:5]2=[O:28]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(OC)c2)c2c(C)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(C)c32)ccc1F
Yield: 96.4 %

Procedure:
Ethyl 6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (400 mg) was added to a mixed liquid (1:1, v/v; 4 ml) of 2N hydrochloric acid and acetic acid, and the mixture was stirred and heated under reflux for 5 hours. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (358 mg) as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH2:14][C:15]1[C:24]2[C:19](=[C:20](Br)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]>>[NH2:14][C:15]1[C:24]2[C:19](=[C:20]([C:8]3[CH:9]=[CH:10][C:5]4[N:4]=[CH:3][N:2]([CH3:1])[C:6]=4[CH:7]=3)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]
Reactant: Cn1cnc2ccc(B(O)O)cc21
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2ncn(C)c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using (1-methyl-1H-benzo[d]imidazol-6-yl)boronic acid and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3 H), 3.83 (s, 3 H), 7.11 (dd, J=8.34, 1.52 Hz, 1 H), 7.49 (d, J=1.01 Hz, 1 H), 7.55 (br s, 1 H), 7.72 (t, J=8.46 Hz, 2 H), 8.22 (s, 1 H), 8.35 (s, 1 H), 8.37 (s, 1 H); ESI-MS m/z [M+H]+ 333.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:19]=[C:20]([CH3:28])[C:21]3[N:22]([C:24]([CH3:27])=[N:25][N:26]=3)[CH:23]=2)=[CH:4][CH:3]=1.I[CH:30]1[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]1>>[NH:32]1[CH2:33][CH:30]([N:12]2[C:11]3[C:10](=[O:17])[N:9]([C:18]4[CH:19]=[C:20]([CH3:28])[C:21]5[N:22]([C:24]([CH3:27])=[N:25][N:26]=5)[CH:23]=4)[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:15]=3[C:14]([CH3:16])=[N:13]2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Product: Cc1nn(C2CNC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared using an analogous procedure to that described in Example 134 using 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 98) (750 mg, 1.909 mmol) and stirring the reaction mixture for 30 min at 80° C. after addition of tert-butyl 3-iodoazetidine-1-carboxylate. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%) followed by preparative HPLC (Gilson gx-281. Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient: 5% to 60% B in 20 min; A=0.1% TFA in H2O, B=CH3CN. Detection: UV) to afford:
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C@@H:11]([NH2:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].[CH3:22][C:23]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)([CH3:27])[C:24](O)=[O:25].Cl.C(N=C=NCCCN(C)C)C.N1C=CC=CC=1>C(#N)C>[C:2]([C:4]1[CH:5]=[C:6]([CH:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[CH:11]([NH:13][C:24](=[O:25])[C:23]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)([CH3:27])[CH3:22])[CH3:12])[CH:7]=[CH:8][CH:9]=1)#[N:3]
Reactant: C[C@H](N)[C@@H](Cc1ccc(O)cc1)c1cccc(C#N)c1
Reactant: Cc1ccc(OC(C)(C)C(=O)O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(OC(C)(C)C(=O)NC(C)C(Cc2ccc(O)cc2)c2cccc(C#N)c2)nc1
Temperature: 25 °C

Procedure:
To a solution of N-(1S, 2S)-[2-(3-cyanophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]amine hydrochloride (Reference Example 8, 0.17 g, 0.49 mmol), 2-methyl-2-(5-methyl-2-pyridyloxy)propionic acid (Reference Example 12, 96 mg, 0.49 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.11 g, 0.59 mmol) in acetonitrile (2 mL) at 0° C. was added pyridine (91 uL, 1.1 mmol). The reaction was allowed to warm up to room temperature overnight, and was quenched with saturated with sodium bicarbonate (2 mL). The resulting mixture was partitioned between tert-butyl methyl ether (20 mL) and water (20 mL). The organic layer was separated, washed with 1 M hydrochloric acid, water and brine and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 10 to 70% ethyl acetate in hexane to afford N-[2-(3-Cyano-phenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylpropanamide. 1H NMR (500 MHz, CD3OD): δ 7.85 (br d, 1H), 7.81 (d, 1H), 7.53-7.80 (m, 2H), 7.38 (t, 1H), 7.34 (br d, 1H), 7.32 (br s, 1H), 6.80 (d, 1H), 6.51 (ABq, 4H), 4.26 (m, 1H), 3.01 (dd, 1H), 2.81 (td, 1H), 2.54 (dd, 1H), 2.12 (s, 3H), 1.73 (s, 3H), 1.67 (s, 3H), 0.83 (d, 3H). LC-MS: m/e 444 (M+H)+ (3.3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[S:11][C:12]=2[CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>>[C:26]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:10]2[S:11][C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:22][CH:21]=1)(=[O:28])[CH3:27]
Reactant: O=C(O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)c(CC(=O)O)s2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
4-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-thiazole-5-acetic acid (7.0 g, 0.016 moles) was dissolved in 0.1 N sodium hydroxide (493 ml, 0.372 moles) and cooled to 0° C. Acetic anhydride (1.5 ml, 0.016 moles) was added and the mixture left standing at room temperature for 3 hours. To the solution was added dilute hydrochloric acid and the resulting precipitate was filtered off, washed with a little water, dried and recrystallised from methylethylketone to give 2-(4-acetoxyphenyl)-4-(4-chlorophenyl)thiazole-5-acetic acid as a colourless solid (2.4 gm), m.p. 177°-180° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)[N:12]=1.[CH3:28][C:29]([CH3:31])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:29]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)[N:12]=1)([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: CC(Nc1cc(-c2csc(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cs1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 75 mg (0.2 mmol) {4-[2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.15 mL (2mmol) acetone, 120 mg (2 mmol) NaBH3(CN) and 1 mL methanol consequently. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, obtained the title compound as a yellow solid. MS (ES+): 420 (M+H)+.
Reaction SMILES: COC(=O)C(CC(OC(C)(C)C)=O)=C.C[O:16][P:17]([CH:33]([NH:35]C(OCC1C=CC=CC=1)=O)[CH3:34])([CH2:19][CH:20]([C:29]([O:31]C)=[O:30])[CH2:21][C:22]([O:24]CCCC)=[O:23])=[O:18].C(OCC)(=O)C>C(#N)C>[NH2:35][CH:33]([P:17]([CH2:19][CH:20]([C:29]([OH:31])=[O:30])[CH2:21][C:22]([OH:24])=[O:23])(=[O:16])[OH:18])[CH3:34]
Reactant: CCCCOC(=O)CC(CP(=O)(OC)C(C)NC(=O)OCc1ccccc1)C(=O)OC
Agent: C=C(CC(=O)OC(C)(C)C)C(=O)OC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(N)P(=O)(O)CC(CC(=O)O)C(=O)O

Procedure:
By methods used in Example 2 and employing methyl-2-t-butoxycarbonylmethylacrylate was prepared methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-3-butoxycarbonyl-1-propyl]phosphinate. TLC (silica, 9:1, ethyl acetate:acetonitrile) Rf =0.58.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[N:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ncn1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C(=O)OC)ncn3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-6-(4-amino-3-methoxypiperidin-1-yl)pyrimidine-4-carboxylate obtained in Example (174d) (53.5 mg, 0.2 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (32 mg, 0.18 mmol), WSC hydrochloride (105 mg, 0.55 mmol) and HOBt (24.7 mg, 0.18 mmol), to obtain 62.2 mg of the title compound as a yellow oily substance (81%).